Epigenetics Podcast: Recent Episodes
Active Motif
In this episode, we speak with Andrea Brand, Chair of the Department of Cell Biology at NYU Grossman School of Medicine and Director of the Regenerative Medicine Institute. We discuss her scientific path from yeast gene regulation to Drosophila neurobiology, and how early interests in DNA and microscopy shaped her career.
We talk about the development of the GAL4 system with Norbert Perrimon and how it enabled targeted gene expression in specific tissues and cells. Andrea explains why this approach has remained useful across decades, including its applications in Drosophila and beyond, while noting that no experimental system is perfect and results should be cross-checked with other methods.
We also discuss targeted DAM-ID and chromatin DAM-ID, methods developed in her lab to study protein-DNA interactions and chromatin marks in vivo without removing cells from their normal tissue environment. Andrea describes how these tools helped her lab analyze neural stem cells in their niche and investigate changes in chromatin during quiescence and reactivation.
A major theme of the conversation is neural stem cell quiescence. We cover how her lab found that quiescent stem cells can show unexpectedly open chromatin, express neuronal genes, and adopt neuron-like features, including long projections and interactions with neurons. We also discuss the link to metabolism, including feeding signals, the fat body, blood-brain barrier glia, insulin-like peptides, and TGF-beta signaling.
Finally, we talk about Andrea’s recent move toward human brain organoids and the goal of connecting model organism work to human biology and patient data. We discuss ongoing work on quiescent cells, TRIB family genes, and cancer–neuron interactions, as well as the need to better distinguish quiescence from senescence in vivo.
References Brand, A. H., & Perrimon, N. (1993). Targeted gene expression as a means of altering cell fates and generating dominant phenotypes. Development (Cambridge, England), 118(2), 401–415. https://doi.org/10.1242/dev.118.2.401 * Southall, T. D., Gold, K. S., Egger, B., Davidson, C. M., Caygill, E. E., Marshall, O. J., & Brand, A. H. (2013). Cell-type-specific profiling of gene expression and chromatin binding without cell isolation: assaying RNA Pol II occupancy in neural stem cells. Developmental cell, 26(1), 101–112. https://doi.org/10.1016/j.devcel.2013.05.020 * Tang, J. L. Y., Hakes, A. E., Krautz, R., Suzuki, T., Contreras, E. G., Fox, P. M., & Brand, A. H. (2022). NanoDam identifies Homeobrain (ARX) and Scarecrow (NKX2.1) as conserved temporal factors in the Drosophila central brain and visual system. Developmental cell, 57(9), 1193–1207.e7. https://doi.org/10.1016/j.devcel.2022.04.008 * Cheetham, S. W., & Brand, A. H. (2018). RNA-DamID reveals cell-type-specific binding of roX RNAs at chromatin-entry sites. Nature structural & molecular biology, 25(1), 109–114. https://doi.org/10.1038/s41594-017-0006-4 * Cheetham, S. W., Gruhn, W. H., van den Ameele, J., Krautz, R., Southall, T. D., Kobayashi, T., Surani, M. A., & Brand, A. H. (2018). Targeted DamID reveals differential binding of mammalian pluripotency factors. Development (Cambridge, England), 145*(20), dev170209. https://doi.org/10.1242/dev.170209
Related Episodes* scDamID, EpiDamID and Lamina Associated Domains (Jop Kind) * Characterizing Chromatin at the Nuclear Lamina (Bas van Steensel)
Contact* Epigenetics Podcast on Mastodon * Epigenetics Podcast on Bluesky * Dr. Stefan Dillinger on LinkedIn * Active Motif on LinkedIn * Active Motif on Bluesky * Email: podcast@activemotif.com
In this episode we speak with Alon Goren from UC San Diego about his work at the intersection of genomic technology development and chromatin biology. We discuss how his lab studies how the epigenome is regulated, how disruption of that regulation contributes to disease, and how technology can be improved to make results more robust and reproducible.
We talk about his early interest in biology, how that developed through medical research training, and how a molecular biology lab shaped the direction of his career. He explains how curiosity about how cells and organisms work led him toward genomics and chromatin research.
We then discuss several methods from his career, including early direct sequencing approaches for small amounts of DNA and RNA, ChIP-based methods for chromatin regulators, and work on improving ChIP-seq workflows. He explains why antibody choice matters, why monoclonal antibodies can improve reproducibility, and how automation helped scale the process.
We also cover his work on spike-in normalization, including the risks of using exogenous chromatin incorrectly and the need for better safeguards in genome-wide comparisons. He describes a newer approach that uses two spike-ins to provide multiple checks on normalization.
Finally, we discuss his work on short tandem repeats, zebrafish heart regeneration, and SIRT6-related polymerase pausing, as well as a newer platform that converts molecular interactions into sequencing-readable barcodes. He closes by stressing the importance of validation, careful protocol design, and methods that can be used reliably by multiple people.
References Ram, O., Goren, A., Amit, I., Shoresh, N., Yosef, N., Ernst, J., Kellis, M., Gymrek, M., Issner, R., Coyne, M., Durham, T., Zhang, X., Donaghey, J., Epstein, C. B., Regev, A., & Bernstein, B. E. (2011). Combinatorial patterning of chromatin regulators uncovered by genome-wide location analysis in human cells. Cell, 147(7), 1628–1639. https://doi.org/10.1016/j.cell.2011.09.057 * Busby, M., Xue, C., Li, C., Farjoun, Y., Gienger, E., Yofe, I., Gladden, A., Epstein, C. B., Cornett, E. M., Rothbart, S. B., Nusbaum, C., & Goren, A. (2016). Systematic comparison of monoclonal versus polyclonal antibodies for mapping histone modifications by ChIP-seq. Epigenetics & chromatin, 9, 49. https://doi.org/10.1186/s13072-016-0100-6 * Patel, L. A., Cao, Y., Mendenhall, E. M., Benner, C., & Goren, A. (2024). The Wild West of spike-in normalization. Nature biotechnology, 42(9), 1343–1349. https://doi.org/10.1038/s41587-024-02377-y * Ben-Yair, R., Butty, V. L., Busby, M., Qiu, Y., Levine, S. S., Goren, A., Boyer, L. A., Burns, C. G., & Burns, C. E. (2019). H3K27me3-mediated silencing of structural genes is required for zebrafish heart regeneration. Development (Cambridge, England), 146(19), dev178632. https://doi.org/10.1242/dev.178632 * Patel, L., Cao, Y., Xu, T., Modolo, E., Dishon, T., Zhang, L., Mendenhall, E., Heinz, S., Simon, I., Benner, C., & Goren, A. (2025). Improved spike-in normalization clarifies the relationship between active histone modifications and transcription. Genomics. https://doi.org/10.1101/2025.11.25.690627 * Xu, T., Wang, J., Shin, Y., Cao, Y., Zhang, L., Modolo, E., Dishon, T., Fisher, J., Norton, M., Fry, C. J., Farjoun, Y., Mendenhall, E., Heinz, S., Benner, C., & Goren, A. (2026). Multiplexed measurements of protein-protein interactions and protein abundance across cellular conditions using Prod&PQ-seq*. Genomics. https://doi.org/10.64898/2026.01.01.697286
Related Episodes* Taking ChIP from Yeast to ENCODE to Enable Genome-Wide Regulatory Protein Mapping (Peggy Farnham) * Comparing CUT&Tag to ENCODE ChIP-Seq in Alzheimer's Disease Samples (Sarah Marzi) * Chromatin Profiling: From ChIP to CUT&RUN, CUT&Tag and CUTAC (Steven Henikoff)
Contact* Epigenetics Podcast on Mastodon * Epigenetics Podcast on Bluesky * Dr. Stefan Dillinger on LinkedIn * Active Motif on LinkedIn * Active Motif on Bluesky * Email: podcast@activemotif.com
In this episode of the Epigenetics Podcast, we talked with Tomohisa Toda from the Max-Planck-Zentrum für Physik und Medizin about his work on the long-term maintenance of neuronal identity, with a focus on epigenetic and RNA-based mechanisms in brain stability and aging.
Dr. Toda describes how brain circuits are stabilized over time, why critical periods are temporally restricted, and how epigenetic regulation may help maintain established neural identity. This led him to postdoctoral work on neural stem cells and long-term maintenance.
We cover his work on nuclear pore and nuclear lamina proteins, including NUP153 and Lamin B1. He explains that NUP153 is enriched in neural stem cells and appears to act as a platform for recruiting factors that help maintain the stem cell epigenome. For Lamin B1, we discuss its decline during aging, how its loss can lead to stem cell exhaustion, reduced adult neurogenesis, and age-related mood dysregulation in the hippocampus.
We also discuss LINE-1 RNA, where we learn that reducing LINE-1 promotes neural progenitor differentiation. He explains that this effect is linked to the RNA sequence itself rather than retrotransposition, based on rescue experiments.
Finally, we talk about his finding that a subset of postnatally born brain cells contains nuclear RNAs that remain detectable for up to two years. He describes their nuclear enrichment, possible association with heterochromatin, and ongoing work to understand their sequence features, modifications, and biological function.
References Bedrosian, T. A., Houtman, J., Eguiguren, J. S., Ghassemzadeh, S., Rund, N., Novaresi, N. M., Hu, L., Parylak, S. L., Denli, A. M., Randolph-Moore, L., Namba, T., Gage, F. H., & Toda, T. (2021). Lamin B1 decline underlies age-related loss of adult hippocampal neurogenesis. The EMBO journal, 40(3), e105819. https://doi.org/10.15252/embj.2020105819 * Zocher, S., McCloskey, A., Karasinsky, A., Schulte, R., Friedrich, U., Lesche, M., Rund, N., Gage, F. H., Hetzer, M. W., & Toda, T. (2024). Lifelong persistence of nuclear RNAs in the mouse brain. Science (New York, N.Y.), 384(6691), 53–59. https://doi.org/10.1126/science.adf3481 * Zhilina, D., Bolaños Castro, L. A., Eguiguren, J. S., Zocher, S., Karasinsky, A., Widmer, D., Espinós, A., Borrell, V., Brand, M., Miura, K., Zierau, O., Yun, M. H., & Toda, T. (2026). Dynamic expression of lamin B1 during adult neurogenesis in the vertebrate brain. Developmental dynamics : an official publication of the American Association of Anatomists, 255*(2), 187–208. https://doi.org/10.1002/dvdy.70023
Related Episodes* Characterizing Chromatin at the Nuclear Lamina (Bas van Steensel) * Single Cell Epigenomics in Neuronal Development (Tim Petros) * The Role of Histone Dopaminylation and Serotinylation in Neuronal Plasticity (Ian Maze)
Contact* Epigenetics Podcast on Mastodon * Epigenetics Podcast on Bluesky * Dr. Stefan Dillinger on LinkedIn * Active Motif on LinkedIn * Active Motif on Bluesky * Email: podcast@activemotif.com
In this episode of the Epigenetics Podcast, we talked with Tae-Kyung Kim from POSTECH in South Korea about the discovery and characterisation of enhancer RNAs.
Dr. Kim describes joining Danny Reinberg’s lab as a graduate student, where he was trained in protein biochemistry and general transcription mechanisms. He recalls this period as a formative time, when research on transcription factors and RNA polymerase II was rapidly advancing and many findings were still novel.
Kim then moved into neurobiology through Michael Greenberg’s lab, where he first worked on a project related to L-type voltage-gated channels. He says his work shifted toward chromatin and gene regulation in neurons after learning that chromatin immunoprecipitation could be applied to neuronal systems and after the arrival of next-generation sequencing.
He explains that eRNAs were discovered in his lab through RNA-seq and ChIP-seq data from neuronal activity experiments, especially around the FOS locus. He later showed that eRNAs are transcribed from enhancers, are typically unstable, often lack splicing and polyadenylation, and have defined initiation sites, suggesting regulated transcription.
Kim says eRNAs can interact with transcription and epigenetic regulators, including factors involved in pause release and mediator complexes. He describes experiments showing that eRNA knockdown reduced ARC induction and that eRNA production depends on proper enhancer-promoter contact.
He concludes by describing newer work in his lab using spatial transcriptomics and eRNA-based reporter systems to map active neural populations, including studies related to cocaine-responsive circuits. He says his future work will focus on spatial technologies to better understand brain organization and function at molecular resolution.
References* Kim TK, Hemberg M, Gray JM, Costa AM, Bear DM, Wu J, Harmin DA, Laptewicz M, Barbara-Haley K, Kuersten S, Markenscoff-Papadimitriou E, Kuhl D, Bito H, Worley PF, Kreiman G, Greenberg ME. Widespread transcription at neuronal activity-regulated enhancers. Nature. 2010 May 13;465(7295):182-7. doi: 10.1038/nature09033. Epub 2010 Apr 14. PMID: 20393465; PMCID: PMC3020079. * Schaukowitch K, Joo JY, Liu X, Watts JK, Martinez C, Kim TK. Enhancer RNA facilitates NELF release from immediate early genes. Mol Cell. 2014 Oct 2;56(1):29-42. doi: 10.1016/j.molcel.2014.08.023. Epub 2014 Sep 25. PMID: 25263592; PMCID: PMC4186258. * Kim SK, Liu X, Park J, Um D, Kilaru G, Chiang CM, Kang M, Huber KM, Kang K, Kim TK. Functional coordination of BET family proteins underlies altered transcription associated with memory impairment in fragile X syndrome. Sci Adv. 2021 May 19;7(21):eabf7346. doi: 10.1126/sciadv.abf7346. PMID: 34138732; PMCID: PMC8133748. * Gorbovytska V, Kim SK, Kuybu F, Götze M, Um D, Kang K, Pittroff A, Brennecke T, Schneider LM, Leitner A, Kim TK, Kuhn CD. Enhancer RNAs stimulate Pol II pause release by harnessing multivalent interactions to NELF. Nat Commun. 2022 May 4;13(1):2429. doi: 10.1038/s41467-022-29934-w. PMID: 35508485; PMCID: PMC9068813.
Related Episodes* Enhancer Communities in Adipocyte Differentiation (Susanne Mandrup) * Enhancer-Promoter Interactions During Development (Yad Ghavi-Helm) * Enhancers and Chromatin Remodeling in Mammary Gland Development (Camila dos Santos)
Contact* Epigenetics Podcast on Mastodon * Epigenetics Podcast on Bluesky * Dr. Stefan Dillinger on LinkedIn * Active Motif on LinkedIn * Active Motif on Bluesky * Email: podcast@activemotif.com
In this episode of the Epigenetics Podcast, we talked with Peter Becker from the Biomedical Center Munich about his successful career in Epigenetics, where he discovered the chromatin remodeler ISWI and dosage compensation complex MOF.
Dr. Becker shares thoughts about his postdoctoral work with Carl Wu, where he developed embryo extract systems for studying chromatin assembly and transcription. He explains how work on Drosophila extracts led to the purification of ATP-dependent remodeling factors, including ISWI-related complexes, and how these studies showed that such factors slide nucleosomes and help organize chromatin.
We also cover his move to EMBL and later to Munich, where his lab expanded into dosage compensation in Drosophila. He describes work on the MSL complex targeting, MRE sequences, ROX RNA, DNA shape features, and how biochemical reconstitution was used to study how the complex recognizes the X chromosome.
Finally, we discuss his later work on TIP-60 and histone acetylation, including acetylome studies, and his reflections on leadership roles at EMBL and on the use of the term epigenetics. He emphasizes that epigenetics should be understood as one layer among genetics, environment, and socialization, not as a replacement for genetics.
References Tsukiyama, T., Becker, P. B., & Wu, C. (1994). ATP-dependent nucleosome disruption at a heat-shock promoter mediated by binding of GAGA transcription factor. Nature, 367(6463), 525–532. https://doi.org/10.1038/367525a0 * Varga-Weisz, P. D., Wilm, M., Bonte, E., Dumas, K., Mann, M., & Becker, P. B. (1997). Chromatin-remodelling factor CHRAC contains the ATPases ISWI and topoisomerase II. Nature, 388(6642), 598–602. https://doi.org/10.1038/41587 * Corona, D. F., Längst, G., Clapier, C. R., Bonte, E. J., Ferrari, S., Tamkun, J. W., & Becker, P. B. (1999). ISWI is an ATP-dependent nucleosome remodeling factor. Molecular cell, 3(2), 239–245. https://doi.org/10.1016/s1097-2765(00)80314-7 * Akhtar, A., & Becker, P. B. (2000). Activation of transcription through histone H4 acetylation by MOF, an acetyltransferase essential for dosage compensation in Drosophila. Molecular cell, 5(2), 367–375. https://doi.org/10.1016/s1097-2765(00)80431-1 * Akhtar, A., Zink, D., & Becker, P. B. (2000). Chromodomains are protein-RNA interaction modules. Nature, 407(6802), 405–409. https://doi.org/10.1038/35030169 * Villa, R., Schauer, T., Smialowski, P., Straub, T., & Becker, P. B. (2016). PionX sites mark the X chromosome for dosage compensation. Nature, 537*(7619), 244–248. https://doi.org/10.1038/nature19338
Related Episodes* Dosage Compensation in Drosophila (Asifa Akhtar) * DNase Hypersensitive Sites and Chromatin Remodeling Enzymes (Carl Wu) * The Mechanism of ATP-dependent Remodelers and HP1 Gene Silencing (Geeta Narlikar) * Regulation of Chromatin Organization by Histone Chaperones (Geneviève Almouzni)
Contact* Epigenetics Podcast on Mastodon * Epigenetics Podcast on Bluesky * Dr. Stefan Dillinger on LinkedIn * Active Motif on LinkedIn * Active Motif on Bluesky * Email: podcast@activemotif.com
In this episode of the Epigenetics Podcast, we talked with Filippo Rijli from the Friedrich Miescher Institute about his work on transcriptional and epigenetic regulation of craniofacial and neuronal development.
Dr. Rijli recalls pivotal moments in his career, including his postdoctoral work where he explored the functions of HoxA2 in craniofacial development. We discuss key findings from his landmark papers, highlighting how individual transcription factors like HoxA2 can dictate the topographic organization of neuronal circuits. His exploration of the whisker-to-barrel cortex circuit in mice unveils how sensory inputs are mapped and processed through precise neuronal connections. This intricate mapping reveals how singular genes can impact the wiring of entire neurological systems.
We also reflect on the evolution of scientific communication throughout Filippo’s career, from the reliance on faxes and handwritten requests for paper reprints to today's instant access to research through digital platforms. His early experiences have instilled in him a resourcefulness that continues to inform his approach to research, particularly in environments with limited resources where collaboration becomes essential.
Our discussion shifts to his recent research endeavors that delve into transcriptional and epigenetic regulation during neuronal and craniofacial development. Dr. Rijli elaborates on a 2015 study which demonstrated how the ectopic expression of HoxA2 could lead to the creation of artificial whisker maps in the brain, providing insights into how transcription factors guide neuronal behavior and circuit formation. His work on the histone methyltransferase EZH2 reveals its crucial role in the tangential migration of cerebellar neurons and the mechanisms that ensure these neurons reach their accurate destinations during development.
Dr. Rijli's research further investigates the chromatin landscape of cranial neural crest cells, uncovering how polycomb group proteins maintain a poised state that enables these cells to respond flexibly to environmental signals. This concept of plasticity is particularly relevant in his latest research on nasal chondrocytes, suggesting that these cells retain developmental potential that may be harnessed in regenerative medicine. The discussions hint at a future where understanding these intricate mechanisms could lead to groundbreaking advancements in treating injuries or diseases.
Throughout the episode, Dr. Rijli’s enthusiasm for discovery is palpable as he shares how each research finding leads to more questions, showcasing the iterative nature of scientific research. This dialogue provides not only a deep dive into his specific studies but also a broader view of how developmental biology continues to evolve, emphasizing the importance of understanding the molecular underpinnings of cellular identity and connectivity.
References Oury, F., Murakami, Y., Renaud, J. S., Pasqualetti, M., Charnay, P., Ren, S. Y., & Rijli, F. M. (2006). Hoxa2- and rhombomere-dependent development of the mouse facial somatosensory map. Science (New York, N.Y.), 313(5792), 1408–1413. https://doi.org/10.1126/science.1130042 * Di Meglio, T., Kratochwil, C. F., Vilain, N., Loche, A., Vitobello, A., Yonehara, K., Hrycaj, S. M., Roska, B., Peters, A. H., Eichmann, A., Wellik, D., Ducret, S., & Rijli, F. M. (2013). Ezh2 orchestrates topographic migration and connectivity of mouse precerebellar neurons. Science (New York, N.Y.), 339(6116), 204–207. https://doi.org/10.1126/science.1229326 * Minoux, M., Holwerda, S., Vitobello, A., Kitazawa, T., Kohler, H., Stadler, M. B., & Rijli, F. M. (2017). Gene bivalency at Polycomb domains regulates cranial neural crest positional identity. Science (New York, N.Y.), 355(6332), eaal2913. https://doi.org/10.1126/science.aal2913 * Kessler, S., Minoux, M., Joshi, O., Ben Zouari, Y., Ducret, S., Ross, F., Vilain, N., Salvi, A., Wolff, J., Kohler, H., Stadler, M. B., & Rijli, F. M. (2023). A multiple super-enhancer region establishes inter-TAD interactions and controls Hoxa function in cranial neural crest. Nature communications, 14*(1), 3242. https://doi.org/10.1038/s41467-023-38953-0
Related Episodes* Chromatin Modifiers and Their Roles in Brain Development (Fides Zenk) * Exploring DNA Methylation and TET Enzymes in Early Development (Petra Hajkova) * The Role of H3K4me3 in Embryonic Development (Eva Hörmanseder)
Contact* Epigenetics Podcast on Mastodon * Epigenetics Podcast on Bluesky * Dr. Stefan Dillinger on LinkedIn * Active Motif on LinkedIn * Active Motif on Bluesky * Email: podcast@activemotif.com
In this episode of the Epigenetics Podcast, we talked with Alena van Bömmel from the Biomedical Center (BMC) in Munich about her work on the development of interpretable epigenetic clocks and statistical models of epigenetic dynamics during aging, and the unique epigenetic signatures associated with various cancers, such as brain tumors or leukemias to detect powerful diagnostic markers or predictors of therapeutic response.
The Interview starts with Dr. van Bömmel sharing her work on co-occurring transcription factors within cell-type specific enhancers, describing the pioneering use of DNA sequencing and its substantial implications in understanding chromatin accessibility. We explore the findings that revealed varying transcription factor interactions across cell types, emphasizing the complexity inherent in gene regulation. Although her research largely remained in silico, its findings paved the way for potential validation through advanced sequencing techniques.
The discussion broadens to encompass Dr. van Bömmel's work on pediatric acute lymphoblastic leukemia, where she elaborates on the epigenetic dynamics observed in patient samples. We discuss her collaboration on a large project that aimed to elucidate the methylation profiles of leukemia patients and how specific epigenetic modifications might indicate cancer subtypes.
As the conversation shifts towards aging, Dr. van Bömmel explains her research on DNA methylation trajectories in mouse models. This work unearthed unexpected patterns of abrupt changes in methylation that correspond to distinct life stages, reflecting the potential applicability of these findings in understanding human aging processes.
Delving further into her innovative research, she introduces 'Methylizer,' a groundbreaking DNA methylation-based classifier designed for brain tumor diagnostics. We examine the rapid diagnostic capabilities this tool offers in surgical contexts, illustrating a paradigm shift in how epigenetic data can inform real-time clinical decisions.
Now at the LMU in Munich, Dr. van Bömmel shares her experiences establishing her lab and her intent to foster a computational-focused research environment that collaborates closely with wet lab scientists. We discuss her aspirations to integrate various layers of epigenetic data through advanced statistical methods and to investigate the aging dynamics of brain cells, specifically in the context of neurodegenerative diseases like Alzheimer’s.
References Van Bömmel, A., Love, M. I., Chung, H.-R., & Vingron, M. (2018). coTRaCTE predicts co-occurring transcription factors within cell-type specific enhancers. PLOS Computational Biology, 14(8), e1006372. https://doi.org/10.1371/journal.pcbi.1006372 * Olecka, M., van Bömmel, A., Best, L., Haase, M., Foerste, S., Riege, K., Dost, T., Flor, S., Witte, O. W., Franzenburg, S., Groth, M., von Eyss, B., Kaleta, C., Frahm, C., & Hoffmann, S. (2024). Nonlinear DNA methylation trajectories in aging male mice. Nature communications, 15(1), 3074. https://doi.org/10.1038/s41467-024-47316-2 * Brändl, B., Steiger, M., Kubelt, C., Rohrandt, C., Zhu, Z., Evers, M., Wang, G., Schuldt, B., Afflerbach, A. K., Wong, D., Lum, A., Halldorsson, S., Djirackor, L., Leske, H., Magadeeva, S., Smičius, R., Quedenau, C., Schmidt, N. O., Schüller, U., Vik-Mo, E. O., … Müller, F. J. (2025). Rapid brain tumor classification from sparse epigenomic data. Nature medicine, 31*(3), 840–848. https://doi.org/10.1038/s41591-024-03435-3
Related Episodes* Evolutionary Epigenetic Clocks and Epigenetic Inheritance in Plants (Frank Johannes) * Epigenetic Clocks and Biomarkers of Ageing (Morgan Levine) * Epigenetic Consequences of DNA Methylation in Development (Maxim Greenberg)
Contact* Epigenetics Podcast on Mastodon * Epigenetics Podcast on Bluesky * Dr. Stefan Dillinger on LinkedIn * Active Motif on LinkedIn * Active Motif on Bluesky * Email: podcast@activemotif.com
In this episode of the Epigenetics Podcast, we talked with Iva Tchasovnikarova from the Wellcome Trust Cancer Research UK Gurdon Institute about her work on heterochromatin formation and epigenetic control.
We begin with Dr. Tchasovnikarova's journey into the field of biology, tracing her roots back to her formative years and the pragmatic guidance of her parents. Despite initial uncertainty about her career path, it was her mother’s passion for teaching biology that ultimately inspired her to pursue a degree in the subject.
As Dr. Tchasovnikarova introduces her current role as a group leader at the Gurdon Institute and an assistant professor at the University of Cambridge, she highlights her early work during her PhD which yielded a first-author publication in Science. She reflects on the serendipitous aspects of this experience, detailing a project where she utilised a novel genetic screening system to uncover a repressor complex named HUSH, a pivotal discovery that has implications for understanding transcriptional repression mechanisms in vertebrates.
The conversation progresses into her postdoctoral research, where she further explored the HUSH complex's role alongside another complex, HUSH2. This expansion of her research reveals fascinating insights into how these complexes interact and their potential significance in regulating gene expression, particularly concerning immune responses to viral infections. Dr. Tchasovnikarova outlines her systematic approach to unraveling these complexities, emphasizing the role of reporter systems and genetic screens in uncovering uncharacterized genes and their functions.
In discussing her transition to starting her own lab, Dr. Tchasovnikarova shares her excitement about utilizing methods she developed during her postdoc to discover new regulatory mechanisms. She describes specific experiments that have led to groundbreaking findings, including the characterization of CRAMP1, a regulator of linker histones, which plays a crucial role in the function of the polycomb repressive complex. The intricate relationships between these elements underscore her commitment to understanding the nuances of epigenetic regulation and genome stability.
References Tchasovnikarova, I. A., Timms, R. T., Matheson, N. J., Wals, K., Antrobus, R., Göttgens, B., Dougan, G., Dawson, M. A., & Lehner, P. J. (2015). GENE SILENCING. Epigenetic silencing by the HUSH complex mediates position-effect variegation in human cells. Science (New York, N.Y.), 348(6242), 1481–1485. https://doi.org/10.1126/science.aaa7227 * Danac, J. M. C., Matthews, R. E., Gungi, A., Qin, C., Parsons, H., Antrobus, R., Timms, R. T., & Tchasovnikarova, I. A. (2024). Competition between two HUSH complexes orchestrates the immune response to retroelement invasion. Molecular cell, 84*(15), 2870–2881.e5. https://doi.org/10.1016/j.molcel.2024.06.020
Related Episodes* Heterochromatin Protein 1 and its Influence on the Structure of Chromatin (Serena Sanulli) * Heterochromatin and Phase Separation (Gary Karpen) * Polycomb and Three-Dimensional Genome Organisation (Oliver Bell)
Contact* Epigenetics Podcast on Mastodon * Epigenetics Podcast on Bluesky * Dr. Stefan Dillinger on LinkedIn * Active Motif on LinkedIn * Active Motif on Bluesky * Email: podcast@activemotif.com
In this episode of the Epigenetics Podcast, we talked with Eva Nogales from UC Berkeley about her work on Cryo-EM and the Dynamics of TFIID and PRC2.
We explore the origins of Dr. Nogales's fascination with biology and how her academic journey shifted from physics into the realms of biophysics and structural biology. She shares the profound impact of her training under physicists who instilled a rigorous, quantitative approach to problem-solving, a perspective that continues to influence her work. The importance of visualization emerges as a central theme, showcasing how critical imagery can foster understanding even amidst complex biological structures.
A particular focus of our discussion centers on the transcription factor complex TFIID, a significant milestone in Dr. Nogales's career. She recalls the challenging journey to uncovering its structure for the first time, which involved navigating numerous technical hurdles. Dr. Nogales details how their innovative approaches led to insights about the conformational flexibility and functional dynamics of TFIID, especially in relation to its interactions with DNA during transcription initiation. The richness of this narrative reflects both the perseverance required in scientific discovery and the serendipity that often accompanies groundbreaking breakthroughs.
Transitioning into the epigenetics realm, Dr. Nogales elucidates the critical role of PRC2 in gene silencing and cellular identity preservation. With a focus on chromatin and nucleosome interactions, we unpack the intricate mechanisms by which PRC2 functions in the context of chromatin remodeling and gene regulation. Dr. Nogales recounts how collaborations and the imaginative contributions of her lab members led to novel research trajectories, particularly the elucidation of structural states of PRC2 bound to chromatin and characterized by novel methodologies developed within her lab.
Further, our discussion touches on Dr. Nogales’s recent findings regarding the nuanced interplay of various cofactors involved in PRC2's regulatory functions. We delve into her exciting projects aiming to bring further clarity to the complex dynamics of chromatin interaction and the distinct forms of PRC2. Dr. Nogales's unyielding commitment to research is mirrored in her ambition to explore unresolved questions surrounding these multifaceted biological processes.
References* Andel F 3rd, Ladurner AG, Inouye C, Tjian R, Nogales E. Three-dimensional structure of the human TFIID-IIA-IIB complex. Science. 1999 Dec 10;286(5447):2153-6. doi: 10.1126/science.286.5447.2153. PMID: 10591646. * Cianfrocco MA, Kassavetis GA, Grob P, Fang J, Juven-Gershon T, Kadonaga JT, Nogales E. Human TFIID binds to core promoter DNA in a reorganized structural state. Cell. 2013 Jan 17;152(1-2):120-31. doi: 10.1016/j.cell.2012.12.005. PMID: 23332750; PMCID: PMC3552382. * Yang Z, Mameri A, Cattoglio C, Lachance C, Florez Ariza AJ, Luo J, Humbert J, Sudarshan D, Banerjea A, Galloy M, Fradet-Turcotte A, Lambert JP, Ranish JA, Côté J, Nogales E. Structural insights into the human NuA4/TIP60 acetyltransferase and chromatin remodeling complex. Science. 2024 Aug 23;385(6711):eadl5816. doi: 10.1126/science.adl5816. Epub 2024 Aug 23. PMID: 39088653.
Related Episodes* Structural Analysis of Nucleosomes During Transcription (Lucas Farnung) * Molecular Mechanisms of Chromatin Modifying Enzymes (Karim-Jean Armache) * From Nucleosome Structure to Function (Karolin Luger)
Contact* Epigenetics Podcast on Mastodon * Epigenetics Podcast on Bluesky * Dr. Stefan Dillinger on LinkedIn * Active Motif on LinkedIn * Active Motif on Bluesky * Email: podcast@activemotif.com
In this episode of the Epigenetics Podcast, we talked with Michaela Frye from he German Cancer Research Center (DKFZ) in Heidelberg about her work on the role of RNA modifications and RNA binding proteins in gene expression and cancer development.
Central to Dr. Frey’s work is the NSUN family of RNA-modifying proteins, which she first encountered during her postdoctoral research. Initially perceived as a DNA methyltransferase, she unwittingly discovered that this family also plays vital roles in RNA methylation. Her exploration revealed that these proteins significantly affect gene stability and translation processes, especially under stress, making them critical players in cancer pathology.
As her research progressed, Frey transitioned into her own lab, where she continued exploring RNA modifications in the context of skin and cancer cells. She emphasizes the critical distinction between the roles of different RNA modifications in various cellular contexts, especially highlighting the differences between steady-state stem cells and those undergoing differentiation or stress responses. Frey's lab investigates how these modifications regulate translational processes, which are essential for cellular adaptation to environmental changes.
Frey further discusses her findings related to the NSUN proteins in stem cell function and their implications for germ cell differentiation in testes. This intricate relationship between RNA modifications and cellular dynamics underscores the significance of epitranscriptomics in understanding cancer treatment resistance and cellular adaptation mechanisms.
Recent findings from her team at DKFZ show a compelling connection between mitochondrial function and RNA modifications in cancer cells. Frey articulates a newfound interest in how these modifications influence cellular responses to cancer therapies, particularly how their regulation may mitigate treatment resistance.
Reflecting on the evolution of RNA modification research, she notes that the field has matured rapidly but acknowledges the challenges posed by abundant yet often contradictory findings. Frey advocates for a clearer understanding of the fundamental functions of distinct RNA modifications to harness their potential in therapeutic contexts effectively.
References* Blanco S, Kurowski A, Nichols J, et al. The RNA-methyltransferase Misu (NSun2) poises epidermal stem cells to differentiate. Plos Genetics. 2011 Dec;7(12):e1002403. DOI: 10.1371/journal.pgen.1002403. PMID: 22144916; PMCID: PMC3228827 * Hussain S, Tuorto F, Menon S, et al. The mouse cytosine-5 RNA methyltransferase NSun2 is a component of the chromatoid body and required for testis differentiation. Molecular and Cellular Biology. 2013 Apr;33(8):1561-1570. DOI: 10.1128/mcb.01523-12. PMID: 23401851; PMCID: PMC3624257 * Blanco S, Bandiera R, Popis M, et al. Stem cell function and stress response are controlled by protein synthesis. Nature. 2016 Jun;534(7607):335-340. DOI: 10.1038/nature18282. PMID: 27306184; PMCID: PMC5040503 * Delaunay S, Pascual G, Feng B, et al. Mitochondrial RNA modifications shape metabolic plasticity in metastasis. Nature. 2022 Jul;607(7919):593-603. DOI: 10.1038/s41586-022-04898-5. PMID: 35768510; PMCID: PMC9300468.
Related Episodes* The Effect of lncRNAs on Chromatin and Gene Regulation (John Rinn) * The Role of lncRNAs in Tumor Growth and Treatment (Sarah Diermeier) * The Role of Small RNAs in Transgenerational Inheritance in C. elegans (Oded Rechavi)
Contact* Epigenetics Podcast on Mastodon * Epigenetics Podcast on Bluesky * Dr. Stefan Dillinger on LinkedIn * Active Motif on LinkedIn * Active Motif on Bluesky * Email: podcast@activemotif.com
In this episode of the Epigenetics Podcast, we talked with Oliver Bell from the University of Southern California in Los Angeles about his work on chromatin-based regulatory systems that encode cellular memory and their implications for development and disease.
The Interview starts with Dr. Bell describing his early career contributions to understanding the functionality of histone methylation in facilitating dosage compensation and gene silencing. His efforts at dissecting the complexities of epigenetic regulation culminate in significant discoveries that highlight the nuanced effects of chromatin adjustments on gene activity and stability across cell divisions.
As we progress, Dr. Bell shares details about his postdoctoral research, where he engineered systems to study chromatin remodeling and the maintenance of transcriptional states through development. His innovative use of induced proximity to manipulate chromatin modifiers offers groundbreaking approaches to understanding how epigenetic states can be established and sustained, alongside the implications for therapeutic strategies in cancer treatment.
An important aspect of our discussion centers on his identification of the ZFP462 protein, which plays a critical role in neurodevelopmental disorders. Dr. Bell outlines his lab's ongoing research into deciphering how this zinc finger protein interacts with enhancers to influence gene regulation in embryonic stem cells and its potential connection to specific diseases. This leads to an engaging dialogue about the relationship between 3D genome organization and epigenetic regulation, focusing on how disruptions in chromatin architecture may affect gene expression.
Towards the end of our conversation, we touch upon the emerging potential of AI in epigenetic research, exploring how advances in technology could facilitate the screening of small molecules targeted at chromatin-modifying complexes. Dr. Bell offers a forward-looking perspective on the future applications of this research, revealing his aspirations for therapeutic developments based on his findings.
References Bell, O., Wirbelauer, C., Hild, M., Scharf, A. N., Schwaiger, M., MacAlpine, D. M., Zilbermann, F., van Leeuwen, F., Bell, S. P., Imhof, A., Garza, D., Peters, A. H., & Schübeler, D. (2007). Localized H3K36 methylation states define histone H4K16 acetylation during transcriptional elongation in Drosophila. The EMBO journal, 26(24), 4974–4984. https://doi.org/10.1038/sj.emboj.7601926 * Hathaway, N. A., Bell, O., Hodges, C., Miller, E. L., Neel, D. S., & Crabtree, G. R. (2012). Dynamics and memory of heterochromatin in living cells. Cell, 149(7), 1447–1460. https://doi.org/10.1016/j.cell.2012.03.052 * Moussa, H. F., Bsteh, D., Yelagandula, R., Pribitzer, C., Stecher, K., Bartalska, K., Michetti, L., Wang, J., Zepeda-Martinez, J. A., Elling, U., Stuckey, J. I., James, L. I., Frye, S. V., & Bell, O. (2019). Canonical PRC1 controls sequence-independent propagation of Polycomb-mediated gene silencing. Nature communications, 10(1), 1931. https://doi.org/10.1038/s41467-019-09628-6 * Yelagandula, R., Stecher, K., Novatchkova, M. et al. ZFP462 safeguards neural lineage specification by targeting G9A/GLP-mediated heterochromatin to silence enhancers. Nat Cell Biol 25, 42–55 (2023). https://doi.org/10.1038/s41556-022-01051-2 * Bsteh, D., Moussa, H.F., Michlits, G. et al. Loss of cohesin regulator PDS5A reveals repressive role of Polycomb loops. Nat Commun* 14, 8160 (2023). https://doi.org/10.1038/s41467-023-43869-w
Related Episodes* Effects of DNA Methylation on Chromatin Structure and Transcription (Dirk Schübeler) * Polycomb Proteins, Gene Regulation, and Genome Organization in Drosophila (Giacomo Cavalli) * Transcription and Polycomb in Inheritance and Disease (Danny Reinberg)
Contact* Epigenetics Podcast on Mastodon * Epigenetics Podcast on Bluesky * Dr. Stefan Dillinger on LinkedIn * Active Motif on LinkedIn * Active Motif on Bluesky * Email: podcast@activemotif.com
In this episode of the Epigenetics Podcast, we talked with Patrick Murphy from Cornell University about his work on gene regulation and cellular identity.
Dr. Murphy's research focuses on the molecular mechanisms that govern gene expression through transcriptional and chromatin-based regulatory networks. At the start of the Interview Dr. Murphy describes an innovative single-molecule analytical approach he developed during his early research. This method enables the simultaneous detection of multiple epigenetic marks and contributes to his foundational studies on chromatin biology. Focusing on chromatin states, he introduces the concept of placeholder nucleosomes which are specialised nucleosomes that play key roles in maintaining a permissive chromatin state and facilitating gene activation during embryonic development.
The discussion further explores Dr. Murphy's transition from studying Drosophila to working with zebrafish, highlighting his focus on chromatin reprogramming during zygotic genome activation. He presents data from his collaborations that reveal intriguing roles for specific chromatin marks, emphasising how these discoveries hold potential for understanding gene expression regulation in both zebrafish and mammalian models.
Dr. Murphy also shares insights into a project investigating the impacts of paternal cigarette smoke on offspring health, which led to an exploration of systemic inflammation responses and their lasting effects on gene expression in the brain. This unique intersection of basic and translational research underlines the wide-ranging implications of his findings.
References Murphy, P. J., Cipriany, B. R., Wallin, C. B., Ju, C. Y., Szeto, K., Hagarman, J. A., Benitez, J. J., Craighead, H. G., & Soloway, P. D. (2013). Single-molecule analysis of combinatorial epigenomic states in normal and tumor cells. Proceedings of the National Academy of Sciences of the United States of America, 110(19), 7772–7777. https://doi.org/10.1073/pnas.1218495110 * Murphy, P. J., Wu, S. F., James, C. R., Wike, C. L., & Cairns, B. R. (2018). Placeholder Nucleosomes Underlie Germline-to-Embryo DNA Methylation Reprogramming. Cell, 172(5), 993–1006.e13. https://doi.org/10.1016/j.cell.2018.01.022 * Park, B. J., Hua, S., Casler, K. D., Cefaloni, E., Ayers, M. C., Lake, R. F., Murphy, K. E., Vertino, P. M., O'Connell, M. R., & Murphy, P. J. (2025). CUT&Tag overcomes biases of ChIP and establishes chromatin patterns for repetitive genomic loci. iScience, 28*(11), 113757. https://doi.org/10.1016/j.isci.2025.113757
Related Episodes* Pioneer Transcription Factors and Their Influence on Chromatin Structure (Ken Zaret) * In Vivo Nucleosome Structure and Dynamics (Srinivas Ramachandran) * Nucleosome Positioning in Cancer Diagnostics (Vladimir Teif)
Contact* Epigenetics Podcast on Mastodon * Epigenetics Podcast on Bluesky * Dr. Stefan Dillinger on LinkedIn * Active Motif on LinkedIn * Active Motif on Bluesky * Email: podcast@activemotif.com
In this episode of the Epigenetics Podcast, we talked with Srinjan Basu from Imperial College London to talk about his work on how chromatin architecture and epigenetic mechanisms orchestrate developmental gene expression programs.
We begin by exploring Dr. Basu's early work at Harvard which involved pioneering Raman-based label-free imaging, allowing the study of chromatin dynamics in live tissue. Here, he tackles technical challenges faced in visualizing DNA interactions, emphasizing the shift from 2D to 3D analysis and the importance of real-time observation of chromatin behavior under various conditions. This segues into his groundbreaking research on single transcription factors interacting with chromatin, revealing subtle but significant changes in the dynamics of gene regulation.
We transition into the complexities of chromatin architecture as Dr. Basu recounts his efforts in mapping the entire mouse genome in single pluripotent cells, unearthing unexpected heterogeneity among cells. This heterogeneity raises intriguing questions about its impact on cellular function, prompting ongoing investigations into chromatin dynamics and the role of remodeling complexes like NuRD in cell fate transitions.
Dr. Basu elucidates how recent studies have begun to bridge the gaps in understanding how transcription factors and chromatin dynamics interact during cellular decisions, particularly emphasizing the influence of mechanical signals and the intrinsic properties of cells. His research underscores the idea that stem cells undergo a preparatory phase for differentiation, highlighting the critical balance of intrinsic and extrinsic factors that govern genetic expression and cellular outcomes.
We also talk about Dr. Basu's current research trajectory, focusing on enhancing imaging techniques to study gene dynamics in tissue contexts relevant to developmental biology and disease states. He illustrates a vision for future projects that integrate advanced imaging tools to investigate transcription factor dynamics and chromatin interactions in live cells and embryos, furthering the understanding of decision-making processes in cellular contexts.
References* Stevens TJ, Lando D, Basu S, et al. 3D structures of individual mammalian genomes studied by single-cell Hi-C. Nature. 2017 Apr;544(7648):59-64. DOI: 10.1038/nature21429. PMID: 28289288; PMCID: PMC5385134. * Basu S, Needham LM, Lando D, et al. FRET-enhanced photostability allows improved single-molecule tracking of proteins and protein complexes in live mammalian cells. Nature Communications. 2018 Jun;9(1):2520. DOI: 10.1038/s41467-018-04486-0. PMID: 29955052; PMCID: PMC6023872.
Related Episodes* Advanced Optical Imaging in 3D Nuclear Organisation (Lothar Schermelleh) * Analysis of 3D Chromatin Structure Using Super-Resolution Imaging (Alistair Boettiger) * Single-Molecule Imaging of the Epigenome (Efrat Shema)
Contact* Epigenetics Podcast on Mastodon * Epigenetics Podcast on Bluesky * Dr. Stefan Dillinger on LinkedIn * Active Motif on LinkedIn * Active Motif on Bluesky * Email: podcast@activemotif.com
In this episode of the Epigenetics Podcast, we talked with Peggy Farnham from the Keck School of Medicine at USC about her work on establishing the ChIP Method in mammalian cells.
In this episode, we dive into the relationship between transcription factors, chromatin dynamics, and gene expression with Professor Peggy Farnham from the Keck School of Medicine at USC. Professor Farnham shares her profound insights into how her groundbreaking research has reshaped our understanding of gene regulation and its implications in cancer. We explore how she has been a pioneer in mapping the genome-wide landscape of regulatory proteins, illuminating the molecular logic behind transcriptional control and its disruption in cancer biology.
The interview starts with her instrumental role in adapting chromatin immunoprecipitation (ChIP) technology from yeast to human cells. Professor Farnham reflects on the technical challenges she faced during this transition, such as the quest for visibility of signals in mammalian systems. Her ability to innovate and troubleshoot challenges led to significant advancements in techniques that allow for the rapid identification of transcription factor binding sites, fundamentally changing the landscape of epigenetic research.
As the discussion progresses, we learn about Professor Farnham's active involvement in the ENCODE project, where she contributed to high-resolution mapping of transcription factors and regulatory elements in human cells. She articulates her appreciation for collaborative efforts in science, highlighting how working within a consortium harnesses the collective expertise of diverse research groups. This collaboration not only bolstered the credibility of the data produced but also propelled the field forward in understanding the complexity of gene regulation.
Through her participation in various projects, such as the Psyc-ENCODE consortium and the Roadmap Epigenome Mapping Consortium, Professor Farnham shares insights into her investigation of epigenetic variations, particularly in relation to complex disorders like schizophrenia. Her findings underscore the nuances of enhancer variability among individuals and the implications for understanding disease mechanisms, thereby advancing our knowledge of genetic regulation and its contributions to diverse biological outcomes.
Moreover, the episode highlights Professor Farnham's reflective understanding of emerging technologies in the field. She discusses the evolution of methods that allow researchers to investigate gene regulation at single-cell resolution, recognizing the significant implications these innovations have for our comprehension of cellular differentiation and the transcriptional landscape.
References* Weinmann AS, Bartley SM, Zhang T, Zhang MQ, Farnham PJ. Use of chromatin immunoprecipitation to clone novel E2F target promoters. Molecular and Cellular Biology. 2001 Oct;21(20):6820-6832. DOI: 10.1128/mcb.21.20.6820-6832.2001. PMID: 11564866; PMCID: PMC99859. * Wells J, Farnham PJ. Characterizing transcription factor binding sites using formaldehyde crosslinking and immunoprecipitation. Methods (San Diego, Calif.). 2002 Jan;26(1):48-56. DOI: 10.1016/s1046-2023(02)00007-5. PMID: 12054904. * Rhie SK, Schreiner S, Witt H, et al. Using 3D epigenomic maps of primary olfactory neuronal cells from living individuals to understand gene regulation. Science Advances. 2018 Dec;4(12):eaav8550. DOI: 10.1126/sciadv.aav8550. PMID: 30555922; PMCID: PMC6292713. * Tak YG, Hung Y, Yao L, et al. Effects on the transcriptome upon deletion of a distal element cannot be predicted by the size of the H3K27Ac peak in human cells. Nucleic Acids Research. 2016 May;44(9):4123-4133. DOI: 10.1093/nar/gkv1530. PMID: 26743005; PMCID: PMC4872074.
Related Episodes* The Effect of lncRNAs on Chromatin and Gene Regulation (John Rinn) * CpG Islands, DNA Methylation, and Disease (Sir Adrian Bird) * The Future of Protein–DNA Mapping (Mitch Guttman) * MLL Proteins in Mixed-Lineage Leukemia (Yali Dou)
Contact* Epigenetics Podcast on Mastodon * Epigenetics Podcast on Bluesky * Dr. Stefan Dillinger on LinkedIn * Active Motif on LinkedIn * Active Motif on Bluesky * Email: podcast@activemotif.com
In this episode of the Epigenetics Podcast, we talked with Will Wang from Sanford Burnham Prebys about his work on muscle stem cell repair, regeneration, and aging, exploring spatial-omics and machine learning.
We begin our conversation by exploring the traditional concepts of spatial biology and how they have evolved to play a critical role in disease research. Dr. Wang recounts his journey from a young student in a family of academics to becoming a leading figure in regenerative biology, highlighting how his early interests in life sciences, natural problem-solving abilities, and inspirations from mentorship set the stage for his current research trajectory.
Throughout the discussion, we uncover key insights on how muscle stem cells transition from a quiescent state to a proliferative state in response to injury and how this dynamic process is governed by the epigenetic landscape and various signalling pathways. Dr. Wang emphasises the impact of external factors—be it microenvironment conditions or metabolic cues—on the fate and function of these stem cells, reflecting on the methodologies used to investigate these processes throughout his career.
He shares fascinating findings from his PhD work, where he explored the regulatory role of transcription factors like PAX-7 in muscle stem cell activation, and how subsequent research developed in his postdoc at Stanford further illuminated the relationship between metabolism and histone acetylation. This pivotal work not only demonstrated how metabolic states dictate epigenetic modifications but also offered potential therapeutic insights for muscle degeneration and repair.
As we move into more recent projects, Dr. Wang discusses the advances in multiplexed spatial proteomics and the insights garnered from a single-cell spatiotemporal atlas of muscle regeneration, which highlight the cellular heterogeneity in muscle tissue. He describes the use of novel computational tools, including neural networks, to uncover the regulatory mechanisms underlying stem cell function, particularly how prostaglandin signalling informs the regeneration process and how age impacts stem cell efficacy. The episode then wraps up with an engaging dialogue about the future implications of Dr. Wang’s work in addressing age-related muscle degradation and broader applications in regenerative medicine.
References Yucel, N., Wang, Y. X., Mai, T., Porpiglia, E., Lund, P. J., Markov, G., Garcia, B. A., Bendall, S. C., Angelo, M., & Blau, H. M. (2019). Glucose Metabolism Drives Histone Acetylation Landscape Transitions that Dictate Muscle Stem Cell Function. Cell Reports, 27(13), 3939-3955.e6. https://doi.org/10.1016/j.celrep.2019.05.092 * Wang, Y. X., Palla, A. R., Ho, A. T. V., Robinson, D. C. L., Ravichandran, M., Markov, G. J., Mai, T., Still, C., Balsubramani, A., Nair, S., Holbrook, C. A., Yang, A. V., Kraft, P. E., Su, S., Burns, D. M., Yucel, N. D., Qi, L. S., Kundaje, A., & Blau, H. M. (2025). Multiomic profiling reveals that prostaglandin E2 reverses aged muscle stem cell dysfunction, leading to increased regeneration and strength. Cell Stem Cell, 32*(7), 1154-1169.e9. https://doi.org/10.1016/j.stem.2025.05.012
Related Episodes* Stem Cell Transcriptional Regulation in Naive vs. Primed Pluripotency (Christa Buecker) * The Effect of Mechanotransduction on Chromatin Structure and Transcription in Stem Cells (Sara Wickström) * Epigenetic Regulation of Stem Cell Self-Renewal and Differentiation (Peggy Goodell)
Contact* Epigenetics Podcast on Mastodon * Epigenetics Podcast on Bluesky * Dr. Stefan Dillinger on LinkedIn * Active Motif on LinkedIn * Active Motif on Bluesky * Email: podcast@activemotif.com
In this episode of the Epigenetics Podcast, we talked with Mitch Guttman from Caltec about ChIP-DIP (ChIP-Done In Parallel).
ChIP-DIP is a newly developed approach for high-resolution protein–DNA interaction mapping. The method uses antibody-guided isolation of denaturant-insoluble protein–DNA complexes, resulting in substantially improved specificity and peak definition compared with conventional ChIP-seq. We explore why denaturation resistance is central to the workflow, how the method performs across transcription factors, chromatin regulators, and histone marks, and what experimental parameters determine its success. The conversation also covers current limitations, practical adoption details, and perspectives on how ChIP-DIP fits into the broader landscape of chromatin profiling technologies.
References Perez, A. A., Goronzy, I. N., Blanco, M. R., Yeh, B. T., Guo, J. K., Lopes, C. S., Ettlin, O., Burr, A., & Guttman, M. (2024). ChIP-DIP maps binding of hundreds of proteins to DNA simultaneously and identifies diverse gene regulatory elements. Nature genetics, 56(12), 2827–2841. https://doi.org/10.1038/s41588-024-02000-5 * Ramani, V. Split-pool barcoding serves up an epigenomic smorgasbord. Nat Genet* 56, 2596–2597 (2024). https://doi.org/10.1038/s41588-024-01980-8
Related Episodes* Split-Pool Recognition of Interactions by Tag Extension (SPRITE) (Mitch Guttman)
Contact* Epigenetics Podcast on Mastodon * Epigenetics Podcast on Bluesky * Dr. Stefan Dillinger on LinkedIn * Active Motif on LinkedIn * Active Motif on Bluesky * Email: podcast@activemotif.com
In this episode of the Epigenetics Podcast, we talked with Fides Zenk from the École polytechnique fédérale de Lausanne about her work on transgenerational inheritance in Drosophila and brain organoids for human development insights.
Dr. Zenk begins by sharing her journey into the field of biology, revealing her childhood fascination with nature and the intricate details of plant development. Her transition from an interest in ecology to a deep dive into molecular biology and gene regulation lays the groundwork for understanding her current research focus. We explore how her early experiences continue to shape her scientific curiosity, particularly her passion for studying cellular changes over time during embryonic development.
As the conversation progresses, Dr. Zenk paints a vivid picture of her work at EPFL, where she combines functional genomics, chromatin profiling, and molecular biology techniques. She elaborates on her initial research during her PhD with Nicola Iovino, where she investigated the transgenerational inheritance of histone modifications in Drosophila. This discussion includes fascinating insights into how histone modifications can carry information across generations and their implications in gene expression regulation during early embryonic stages.
Dr. Zenk also provides a glimpse into her postdoctoral work with Barbara Treutlein, where she shifted focus to human models and quantitative analysis using brain organoids. This segment of the episode reveals her commitment to translating molecular mechanisms to human health, especially in understanding the intricacies of brain development and neurogenesis. She describes how her team mapped dynamic changes in histone modifications during critical developmental stages, integrating various data modalities to build an intricate developmental atlas.
References* Zenk F, Loeser E, Schiavo R, et al. Germ line-inherited H3K27me3 restricts enhancer function during maternal-to-zygotic transition. Science (New York, N.Y.). 2017 Jul;357(6347):212-216. DOI: 10.1126/science.aam5339. PMID: 28706074. * Zenk F, Zhan Y, Kos P, et al. HP1 drives de novo 3D genome reorganization in early Drosophila embryos. Nature. 2021 May;593(7858):289-293. DOI: 10.1038/s41586-021-03460-z. PMID: 33854237; PMCID: PMC8116211. * Zenk F, Fleck JS, Jansen SMJ, et al. Single-cell epigenomic reconstruction of developmental trajectories from pluripotency in human neural organoid systems. Nature Neuroscience. 2024 Jul;27(7):1376-1386. DOI: 10.1038/s41593-024-01652-0. PMID: 38914828; PMCID: PMC11239525.
Related Episodes The Role of Small RNAs in Transgenerational Inheritance in C. elegans (Oded Rechavi) * Mapping the Epigenome: From Arabidopsis* to the Human Brain (Joseph Ecker)
Contact* Epigenetics Podcast on Mastodon * Epigenetics Podcast on Bluesky * Dr. Stefan Dillinger on LinkedIn * Active Motif on LinkedIn * Active Motif on Bluesky * Email: podcast@activemotif.com
In this episode of the Epigenetics Podcast, we talked with Anders Sejr Hansen from MIT about his work on the impact of 3D genome structures on gene expression, the roles of proteins like CTCF and cohesin, and advanced techniques like Region Capture Micro-C for mapping genome organisation.
Dr. Sejr Hansen introduces his research focusing on the relationship between three-dimensional genome structure and function, specifically how these structures can influence gene expression. He elaborates on the importance of transcription factors and the role of looping structures in gene regulation, emphasizing the implications of his work for understanding gene functionality in the context of both development and disease.
The conversation then shifts to discussing loop extrusion and the factors affecting loop stability, primarily CTCF and cohesin. Dr. Sejr Hansen highlights the dynamics of these proteins' binding interactions and how their speeds challenge the notion of stable looping structures in the genome. With a keen interest in CTCF's role, he explains how the protein interacts with DNA and the mechanistic aspects of transcription factor movement, alluding to research findings that reveal that CTCF and cohesin tend to form clusters which may play vital roles in establishing chromatin structure. As the interview progresses, Dr. Sejr Hansen details his transition to leading his own lab at MIT, emphasizing the continuation of his earlier work while expanding into new methodologies for studying chromatin. He underscores the importance of understanding not just the static structures of DNA interactions, but the dynamic nature of these relationships and how they influence gene expression. His lab's recent focus has included using advanced imaging techniques to assess the dynamics of chromatin interactions more precisely.
The discussion then touches on specific findings from Dr. Sejr Hansen's lab regarding the relationship between genome organization and double-strand break repair mechanisms. He emphasizes how the repair machinery can affect chromatin structure and underscores the essential role of cohesin in facilitating effective double-strand break repair by keeping broken DNA ends in proximity. He suggests that loop extrusion might help prevent genetic material from diffusing too far apart and improve the efficiency of repair.
Dr. Sejr Hansen also discusses innovations in genome mapping techniques, particularly the development of Region Capture Micro-C, which facilitates deeper insights into the three-dimensional organization of the genome. This method allows researchers to achieve significantly higher resolution in their analyses compared to traditional 3D genomics techniques like Hi-C. He outlines the technical process and the implications of their findings, especially regarding enhancer-promoter interactions and the surprisingly promiscuous nature of these relationships.
References Anders S Hansen, Iryna Pustova, Claudia Cattoglio, Robert Tjian, Xavier Darzacq (2017) CTCF and cohesin regulate chromatin loop stability with distinct dynamics eLife 6:e25776 https://doi.org/10.7554/eLife.25776 * Claudia Cattoglio, Iryna Pustova, Nike Walther, Jaclyn J Ho, Merle Hantsche-Grininger, Carla J Inouye, M Julius Hossain, Gina M Dailey, Jan Ellenberg, Xavier Darzacq, Robert Tjian, Anders S Hansen (2019) Determining cellular CTCF and cohesin abundances to constrain 3D genome models eLife 8:e40164 https://doi.org/10.7554/eLife.40164 * Goel, V.Y., Huseyin, M.K. & Hansen, A.S. Region Capture Micro-C reveals coalescence of enhancers and promoters into nested microcompartments. Nat Genet* 55, 1048–1056 (2023). https://doi.org/10.1038/s41588-023-01391-1
Related Episodes* Biophysical Modeling of 3-D Genome Organization (Leonid Mirny) * Unraveling Mechanisms of Chromosome Formation (Job Dekker)
Contact* Epigenetics Podcast on Mastodon * Epigenetics Podcast on Bluesky * Dr. Stefan Dillinger on LinkedIn * Active Motif on LinkedIn * Active Motif on Bluesky * Email: podcast@activemotif.com
In this episode of the Epigenetics Podcast, we talked with Vincent Pasque from KU Leuven about his work on the reprogramming of cell identity through epigenetic mechanisms, particularly during early development and cellular reprogramming.
We begin by tracing Vincent's journey into biology, sparked by early childhood experiences in nature and meaningful encounters with inspiring teachers. His fascination with the complexities of biology crystallized during a pivotal moment while listening to a radio segment on epigenetics in the late '90s, which led him to pursue studies in genetics and biochemistry. This formative path brought him to leading institutions, including the prestigious lab of John Gurdon, where he explored the phenomenon of nuclear reprogramming. Vincent recounts his early experiments that led to the discovery of macro H2A as a barrier to reprogramming, emphasizing the core challenge of erasing somatic cell identity.
As the conversation unfolds, Vincent introduces us to critical findings from his research. He shares how the inactive X chromosome serves as a compelling model to investigate epigenetic regulation, revealing that the dynamics of reprogramming and differentiation are far from simple reversals of development. He highlights the significant differences between male and female iPSCs and how X-linked genes influence DNA methylation and differentiation rates in these cells. The implications of these findings extend beyond developmental biology to inform our understanding of diseases, particularly cancer.
Transitioning to his current work, Vincent describes pioneering advances in characterizing the chromatin-associated proteome during the differentiation of human pluripotent stem cells. The surprising discovery of elevated histone modifications in naïve cells leads to intriguing questions about the barriers to cellular plasticity and the mechanisms by which cells resist alternative fate conversions. The potential applications of this research could reshape our approach to regenerative medicine and therapeutic interventions.
References Pasque V, Gillich A, Garrett N, Gurdon JB. Histone variant macroH2A confers resistance to nuclear reprogramming. The EMBO Journal. 2011 May;30(12):2373-2387. DOI: 10.1038/emboj.2011.144. PMID: 21552206; PMCID: PMC3116279. * Jullien, J., Miyamoto, K., Pasque, V., Allen, G. E., Bradshaw, C. R., Garrett, N. J., Halley-Stott, R. P., Kimura, H., Ohsumi, K., & Gurdon, J. B. (2014). Hierarchical Molecular Events Driven by Oocyte-Specific Factors Lead to Rapid and Extensive Reprogramming. Molecular Cell, 55*(4), 524–536. https://doi.org/10.1016/j.molcel.2014.06.024 * Pasque V, Tchieu J, Karnik R, et al. X chromosome reactivation dynamics reveal stages of reprogramming to pluripotency. Cell. 2014 Dec;159(7):1681-1697. DOI: 10.1016/j.cell.2014.11.040. PMID: 25525883; PMCID: PMC4282187. * Zijlmans DW, Talon I, Verhelst S, et al. Integrated multi-omics reveal polycomb repressive complex 2 restricts human trophoblast induction. Nature Cell Biology. 2022 Jun;24(6):858-871. DOI: 10.1038/s41556-022-00932-w. PMID: 35697783; PMCID: PMC9203278.
Related Episodes* The Discovery of Genomic Imprinting (Azim Surani) * Gene Expression Control and Intricacies of X-chromosome Inactivation (Claire Rougeulle) * Epigenetics and X-Inactivation (Edith Heard)
Contact* Epigenetics Podcast on Mastodon * Epigenetics Podcast on Bluesky * Dr. Stefan Dillinger on LinkedIn * Active Motif on LinkedIn * Active Motif on Bluesky * Email: podcast@activemotif.com
In this episode of the Epigenetics Podcast, we talked with Ryan Corces from the Gladstone Institutes about his work on the impact of chromatin architecture on Alzheimer's and Parkinson's Disease.
The discussion begins in discussing he start of Dr. Corces research career and he shares his groundbreaking findings in acute myeloid leukemia (AML), demonstrating how mutations occurring in hematopoietic stem cells lead to the evolution of this disease. He emphasizes the pivotal role of epigenetic modifiers and how these insights steered his focus towards epigenetic research.
As the conversation progresses, Dr. Corces covers his transition to a postdoctoral role, emphasizing his collaborative work employing the ATAC-seq technique. He details how refinements to this protocol not only improved data quality but also paved the way for more expansive research within the fields of hematology and cancer genetics. Additionally, he discusses his excitement for developing new computational tools for single-cell analysis, aiming to address the critical challenge of distinguishing between cellular states effectively.
The episode also explores the fascinating intersection of Alzheimer’s and Parkinson’s diseases. Dr. Corces explains the rationale for studying both conditions simultaneously, shedding light on the shared and divergent pathological features that emerge in patients. He argues for the importance of understanding mixed pathologies, which reflect the reality for many individuals diagnosed with these neurodegenerative diseases.
References Corces, M. R., Trevino, A. E., Hamilton, E. G., Greenside, P. G., Sinnott-Armstrong, N. A., Vesuna, S., Satpathy, A. T., Rubin, A. J., Montine, K. S., Wu, B., Kathiria, A., Cho, S. W., Mumbach, M. R., Carter, A. C., Kasowski, M., Orloff, L. A., Risca, V. I., Kundaje, A., Khavari, P. A., Montine, T. J., … Chang, H. Y. (2017). An improved ATAC-seq protocol reduces background and enables interrogation of frozen tissues. Nature methods, 14(10), 959–962. https://doi.org/10.1038/nmeth.4396 * Corces, M. R., Granja, J. M., Shams, S., Louie, B. H., Seoane, J. A., Zhou, W., Silva, T. C., Groeneveld, C., Wong, C. K., Cho, S. W., Satpathy, A. T., Mumbach, M. R., Hoadley, K. A., Robertson, A. G., Sheffield, N. C., Felau, I., Castro, M. A. A., Berman, B. P., Staudt, L. M., Zenklusen, J. C., … Chang, H. Y. (2018). The chromatin accessibility landscape of primary human cancers. Science (New York, N.Y.), 362(6413), eaav1898. https://doi.org/10.1126/science.aav1898 * Corces, M. R., Trevino, A. E., Hamilton, E. G., Greenside, P. G., Sinnott-Armstrong, N. A., Vesuna, S., Satpathy, A. T., Rubin, A. J., Montine, K. S., Wu, B., Kathiria, A., Cho, S. W., Mumbach, M. R., Carter, A. C., Kasowski, M., Orloff, L. A., Risca, V. I., Kundaje, A., Khavari, P. A., Montine, T. J., … Chang, H. Y. (2017). An improved ATAC-seq protocol reduces background and enables interrogation of frozen tissues. Nature methods, 14(10), 959–962. https://doi.org/10.1038/nmeth.4396 * Sant, C., Mucke, L., & Corces, M. R. (2025). CHOIR improves significance-based detection of cell types and states from single-cell data. Nature genetics, 57*(5), 1309–1319. https://doi.org/10.1038/s41588-025-02148-8
Related Episodes* ATAC-Seq, scATAC-Seq and Chromatin Dynamics in Single-Cells (Jason Buenrostro) * Multiple challenges of ATAC-Seq, Points to Consider (Yuan Xue)
Contact* Epigenetics Podcast on Mastodon * Epigenetics Podcast on Bluesky * Dr. Stefan Dillinger on LinkedIn * Active Motif on LinkedIn * Active Motif on Bluesky * Email: podcast@activemotif.com
In this episode of the Epigenetics Podcast, we talked with Mo Motamedi from the Center for Cancer Research at Massachusetts General Hospital about his work on RNA-mediated epigenetic regulation.
The Interview starts with Dr. Motamedi sharing his personal journey into the realm of biology, sparked by a familial inclination towards science and a challenge to excel in a field that initially felt daunting. His passion was ignited during a genetics class, as he recognized the quantitative nature of the discipline amidst the evolution of modern techniques like qPCR and high-throughput sequencing.
Dr. Motamedi goes on to articulate the importance of understanding the interplay between genetics and broader biological systems, emphasizing that an insightful grasp of evolution is vital for decoding cellular mechanisms. He reflects on his time in a postdoctoral lab under Danesh Moazed, investigating RNA interference (RNAi) and its unexpected nuclear roles, contributing significantly to the understanding of how RNAi is involved in gene silencing via chromatin interaction.
As his narrative unfolds, Dr. Motamedi provides deep insights into his own lab's work, which focuses on the establishment and maintenance of epigenetic states and their implications in cancer epigenetics. He discusses groundbreaking discoveries related to RNAi and heterochromatin, detailing experiments that unveil how specific proteins contribute to transcriptional and post-transcriptional gene silencing. A pivotal theme emerges: the complex dynamics of genome evolution and chromatin organization can be reshaped under various biological contexts, including the quiescent state of cells under stress.
Moreover, the discussion traverses recent publications from Dr. Motamedi's lab, revealing how they identify long non-coding RNAs that function as silencers at centromeres, an essential mechanism that aids in the establishment of heterochromatin independently of RNAi. His findings advocate for the idea that well-structured genome organization can lead to more efficient gene regulation, which can also be crucial in therapeutic contexts for various cancers.
References Motamedi, M. R., Hong, E. J., Li, X., Gerber, S., Denison, C., Gygi, S., & Moazed, D. (2008). HP1 proteins form distinct complexes and mediate heterochromatic gene silencing by nonoverlapping mechanisms. Molecular cell, 32(6), 778–790. https://doi.org/10.1016/j.molcel.2008.10.026 * Joh RI, Khanduja JS, Calvo IA, Mistry M, Palmieri CM, Savol AJ, Hoi Sui SJ, Sadreyev RI, Aryee MJ, and Motamedi M. Survival in quiescence requires the euchromatic deployment of Clr4/SUV39H by argonaute-associated small RNAs. † Mol Cell. 2016; 64: 1088-1101. * J. S. Khanduja, R. I. Joh, M. M. Perez, J. A. Paulo, C. M. Palmieri, J. Zhang, A. O. D. Gulka, W. Haas, S.P. Gygi, M. Motamedi. RNA quality control factors nucleate Clr4/SUV39H and trigger constitutive heterochromatin assembly. Cell 2024. 187: 3262-3283. Equal contributions * R. I. Joh, M. S. Lawrence, M. J. Aryee, M. Motamedi. Gene clustering drives the transcriptional coherence of disparate biological pathways in eukaryotes. bioRxiv 2023. doi: 10.1101/2021.04.17.440292 co-corresponding authors. * J. S. Khanduja, M. Motamedi. Protocol for the development and use of spike-in control for chromatin immunoprecipitation (ChIP) of chromatin-binding proteins. Star Protocol 2025. 6: 104007. * J. S. Khanduja, M. Motamedi. Protocol for chromatin immunoprecipitation of chromatin-binding proteins in Schizosaccharomyces pombe using a dual-crosslinking approach. Star Protocol* 2025. 6: 103695.
Related Episodes* Evolutionary Forces Shaping Mammalian Gene Regulation (Emily Wong) * Chromatin Evolution (Arnau Sebé-Pedrós) * The Role of lncRNAs in Tumor Growth and Treatment (Sarah Diermeier)
Contact* Epigenetics Podcast on Mastodon * Epigenetics Podcast on Bluesky * Dr. Stefan Dillinger on LinkedIn * Active Motif on LinkedIn * Active Motif on Bluesky * Email: podcast@activemotif.com *
In this episode of the Epigenetics Podcast, we talked with Emily Wong from the University of New South Wales in Sydney about her work on how evolution shapes mammalian genes.
As the head of the Regulatory Systems Lab at the Victor Chang Cardiac Research Institute and an associate professor at UNSW, Emily’s research centers on gene control and enhancers. We delve into her pivotal 2017 publication in Nature Communications, where she investigated transcription factor binding in liver-specific contexts, shedding light on the regulatory mechanisms at play in mammals.
Emily elaborates on her postdoctoral work at the European Bioinformatics Institute and the innovative hybrid systems she used to dissect genetic variation effects, which allowed her to differentiate between cis-regulatory and trans-regulatory influences. By employing techniques like ChIP-seq, she was able to illustrate the combinatorial effects of transcription factors on gene expression, paving the way for her collaborative efforts across disciplines and organisms.
We also examine Emily's findings regarding enhancer function through comparative studies between zebrafish and marine sponges. Using historical data on conserved genetic sequences, she and her team identified enhancer regions that displayed activity in specific vertebrate cell types, despite their evolutionary divergence from sponges. This unexpected result suggests deeper insights into how enhancers can be co-opted for new functions as species evolve.
Furthermore, we dive into Emily's latest ventures involving advanced methodologies such as chromatin accessibility profiling with ATAC-seq and how these insights can elucidate the genomic landscape of metazoan embryogenesis. She highlights significant correlations between enhancer turnover and DNA replication timing, suggesting evolutionary implications that should be taken into account in future genomic studies.
References Wong, E. S., Zheng, D., Tan, S. Z., Bower, N. I., Garside, V., Vanwalleghem, G., Gaiti, F., Scott, E., Hogan, B. M., Kikuchi, K., McGlinn, E., Francois, M., & Degnan, B. M. (2020). Deep conservation of the enhancer regulatory code in animals. Science, 370(6517), eaax8137. https://doi.org/10.1126/science.aax8137 * Cornejo-Páramo, P., Petrova, V., Zhang, X. et al. Emergence of enhancers at late DNA replicating regions. Nat Commun* 15, 3451 (2024). https://doi.org/10.1038/s41467-024-47391-5
Related Episodes* Ultraconserved Enhancers and Enhancer Redundancy (Diane Dickel) * Enhancer Communities in Adipocyte Differentiation (Susanne Mandrup) * Enhancer-Promoter Interactions During Development (Yad Ghavi-Helm)
Contact* Epigenetics Podcast on Mastodon * Epigenetics Podcast on Bluesky * Dr. Stefan Dillinger on LinkedIn * Active Motif on LinkedIn * Active Motif on Bluesky * Email: podcast@activemotif.com
In this episode of the Epigenetics Podcast, we talked with Arnau Sebé-Pedrós from the Center for Genomic Regulation in Barcelona about his work on chromatin evolution.
The Interview starts by examining specific research findings, including his seminal 2018 paper demonstrating whole-organism single-cell transcriptomics to map larval and adult cell types in the model organism Nematostella vectensis. Dr. Sebe-Pedros recounted the challenges and triumphs faced when delving into single-cell studies of non-model organisms, revealing the innovative strategies employed in the lab to overcome these hurdles.
Shifting gears, we touched upon his work comparing cell types and molecular pathways in reef-building corals through single-cell RNA sequencing, contributing to our understanding of evolutionary conservation and divergence within the cnidarian lineage. We discussed how this comparative approach not only adds to knowledge about coral biology but also enhances methodological frameworks in ecological studies.
In addition, Dr. Sebe-Pedros shared insights into ongoing efforts to reconstruct eukaryotic chromatin evolution using comparative proteomics and genomics analysis, as well as the mechanisms of genomic regulation in various species. His reflections on the sharing of experimental insights across research groups illustrated the collaborative spirit prevalent in the scientific community, particularly regarding endeavors like the Biodiversity Cell Atlas consortium aimed at expanding single-cell efforts across the tree of life.
The episode culminated with Dr. Sebe-Pedros’s thoughts on the revolutionary impact of functional genomic technologies and the vast potential they hold for answering longstanding questions in evolutionary biology. With an emphasis on epigenetics, he defined this field as encompassing any information not encoded directly in the DNA, especially in its role in establishing cell identity and differentiation.
References https://www.biodiversitycellatlas.org * Sebé-Pedrós, A., Saudemont, B., Chomsky, E., Plessier, F., Mailhé, M. P., Renno, J., Loe-Mie, Y., Lifshitz, A., Mukamel, Z., Schmutz, S., Novault, S., Steinmetz, P. R. H., Spitz, F., Tanay, A., & Marlow, H. (2018). Cnidarian Cell Type Diversity and Regulation Revealed by Whole-Organism Single-Cell RNA-Seq. Cell, 173(6), 1520–1534.e20. https://doi.org/10.1016/j.cell.2018.05.019 * Sebé-Pedrós, A., Chomsky, E., Pang, K., Lara-Astiaso, D., Gaiti, F., Mukamel, Z., Amit, I., Hejnol, A., Degnan, B. M., & Tanay, A. (2018). Early metazoan cell type diversity and the evolution of multicellular gene regulation. Nature ecology & evolution, 2(7), 1176–1188. https://doi.org/10.1038/s41559-018-0575-6 * Kim, I.V., Navarrete, C., Grau-Bové, X. et al. Chromatin loops are an ancestral hallmark of the animal regulatory genome. Nature* 642, 1097–1105 (2025). https://doi.org/10.1038/s41586-025-08960-w
Related Episodes* Evolutionary Epigenetic Clocks and Epigenetic Inheritance in Plants (Frank Johannes) * Neuroepigenetic Mechanisms and Primate Epigenome Evolution (Boyan Bonev) * Transposable Elements in Gene Regulation and Evolution (Marco Trizzino)
Contact* Epigenetics Podcast on Mastodon * Epigenetics Podcast on Bluesky * Dr. Stefan Dillinger on LinkedIn * Active Motif on LinkedIn * Active Motif on Bluesky * Email: podcast@activemotif.com
In this episode of the Epigenetics Podcast, we talked with Luca Magnani from Institute of Cancer Research and UNIMI in Milan about his work on epigenetic mechanisms of drug resistance and cancer cell dormancy in breast cancer.
We start the interview by putting our focus on his significant contributions to the understanding of estrogen receptor-positive breast cancer. In a foundational study from 2013, Professor Magnani and his colleagues illuminated the role of genome-wide reprogramming of the chromatin landscape in conferring resistance to endocrine therapy. This research marked a departure from a purely genetic mutation paradigm, proposing instead that epigenetic modifications play a pivotal role in the development of drug resistance.
A fascinating part of our conversation centers on the role of pioneer transcription factors, particularly PBX1, in regulating the estrogen receptor's transcriptional response. Professor Magnani explains how PBX1, typically associated with hematopoietic development, influences estrogen receptor activity, thereby shaping the cancer cell's fate and response to treatment.
Continuing our exploration, we discuss the critical distinctions between primary and metastatic breast cancer through the lens of epigenetic reprogramming. By analyzing samples from women with breast cancer, Professor Magnani's work identifies specific enhancer usage that marks the transition to a drug-resistant state which was a breakthrough in linking epigenetic alterations to real-world patient outcomes. He emphasizes that the reliance on genetic mutations alone does not adequately explain the mechanisms of drug resistance, pushing the field to consider the epigenetic landscape more deeply.
Our conversation also touches on the evolution of experimental techniques. Professor Magnani shares insights into the transition from traditional ChIP-seq methods to CUT&RUN, demonstrating the need for techniques that cater to the limited material available from clinical samples. This adaptability mirrors the dynamic nature of cancer itself, as cells continuously evolve under therapeutic pressure.
As we traverse through the complexities of dormancy and reactivation in cancer cells, Professor Magnani enlightens us on the unpredictable nature of tumor behavior. He describes how cancer cells can enter dormant states and how their awakening is influenced by environmental factors, akin to an evolutionary response to stressors, thus revealing the intricate balance between survival and proliferation.
In the latter part of the episode, we explore Professor Magnani's vision for the future of breast cancer research, which includes the need for better animal models that mimic human disease. His pursuit of understanding estrogen receptor behavior both in healthy and cancerous cells reflects a holistic approach to cancer biology, aiming to decipher the transition from normal tissue to malignancy.
References Magnani, L., Stoeck, A., Zhang, X., Lánczky, A., Mirabella, A. C., Wang, T. L., Gyorffy, B., & Lupien, M. (2013). Genome-wide reprogramming of the chromatin landscape underlies endocrine therapy resistance in breast cancer. Proceedings of the National Academy of Sciences of the United States of America, 110(16), E1490–E1499. https://doi.org/10.1073/pnas.1219992110 * Nguyen, V. T., Barozzi, I., Faronato, M., Lombardo, Y., Steel, J. H., Patel, N., Darbre, P., Castellano, L., Győrffy, B., Woodley, L., Meira, A., Patten, D. K., Vircillo, V., Periyasamy, M., Ali, S., Frige, G., Minucci, S., Coombes, R. C., & Magnani, L. (2015). Differential epigenetic reprogramming in response to specific endocrine therapies promotes cholesterol biosynthesis and cellular invasion. Nature communications, 6, 10044. https://doi.org/10.1038/ncomms10044 * Patten, D. K., Corleone, G., & Magnani, L. (2018). Chromatin Immunoprecipitation and High-Throughput Sequencing (ChIP-Seq): Tips and Tricks Regarding the Laboratory Protocol and Initial Downstream Data Analysis. Methods in molecular biology (Clifton, N.J.), 1767*, 271–288. https://doi.org/10.1007/978-1-4939-7774-1_15
Related Episodes* Enhancers and Chromatin Remodeling in Mammary Gland Development (Camila dos Santos) * Contribution of Estrogen Receptor to Breast Cancer Progression (Jason Carroll) * Circulating Epigenetic Biomarkers in Cancer (Charlotte Proudhon)
Contact* Epigenetics Podcast on Mastodon * Epigenetics Podcast on Bluesky * Dr. Stefan Dillinger on LinkedIn * Active Motif on LinkedIn * Active Motif on Bluesky * Email: podcast@activemotif.com
In this episode of the Epigenetics Podcast, we talked with Erica Korb from the University of Pennsylvania about her work on BRD4 and the histone variant H2BE, which influences synaptic genes and neuronal activity.
Dr. Korb discusses the focus of her lab, which centers on epigenetic mechanisms impacting gene regulation in neurons. Her research primarily examines histone biology and its connection to neurodevelopmental disorders, including autism spectrum disorder and intellectual disabilities. Dr. Korb expounds on the collaborative environment at UPenn’s Epigenetics Institute, emphasizing how the rich diversity of research topics fosters innovative ideas and projects within the community.
Reflecting on her earlier work from her postdoctoral studies, Dr. Korb discusses her first significant findings regarding the protein BRD4. This work demonstrated BRD4's role in mediating transcriptional regulation crucial for learning and memory processes. She explains how disrupting this protein's function in neurons hindered critical gene activations required for memory formation in mice. This foundational understanding opened avenues for exploring the broader implications of chromatin regulation in various neurodevelopmental conditions.
Transitioning into her current research endeavors, Dr. Korb reveals how she aims to expand her focus beyond Fragile X syndrome. With her lab now investigating multiple chromatin regulators implicated in various forms of autism spectrum disorders, she describes a recent project where RNA sequencing exposed substantial overlaps in gene expression changes associated with five distinct chromatin modifiers, each contributing uniquely to neuronal function while collectively demonstrating sensitivity to chromatin disruptions.
A significant portion of the discussion centers around Dr. Korb’s unexpected exploration into how COVID-19 intersects with chromatin biology through a phenomenon known as histone mimicry. Leveraging bioinformatic tools during the pandemic, her lab discovered that certain viral proteins mimic histone sequences, which may lead to altered transcriptional outputs in host cells. This coincidental finding illustrates both the creative adaptability needed in scientific research and the importance of collaborative efforts across disciplines to uncover new insights.
The conversation also delves into Dr. Korb’s recent work regarding the histone variant H2BE, initiated by one of her graduate students. She explains how prior research only recognized H2BE's expression in the olfactory system, yet her lab has demonstrated its significant role in regulating synaptic genes and memory formation throughout broader neuronal contexts. Notably, they identified a single amino acid change that influences H2BE's function in chromatin accessibility and gene transcription, emphasizing its potential evolutionary conservation across species.
In terms of H2BE's role, Dr. Korb elucidates that its activity is integral in response to extracellular stimuli, particularly within the context of neuronal activation. Intriguingly, they found that H2BE expression decreases in reaction to long-term neuronal stimulation, suggesting a complex mechanism of homeostatic plasticity crucial for regulating neuronal activity levels. This research not only advances understanding of chromatin dynamics but also holds implications for neuronal health and disease mechanisms.
References Feierman, E. R., Louzon, S., Prescott, N. A., Biaco, T., Gao, Q., Qiu, Q., Choi, K., Palozola, K. C., Voss, A. J., Mehta, S. D., Quaye, C. N., Lynch, K. T., Fuccillo, M. V., Wu, H., David, Y., & Korb, E. (2024). Histone variant H2BE enhances chromatin accessibility in neurons to promote synaptic gene expression and long-term memory. Molecular cell, 84(15), 2822–2837.e11. https://doi.org/10.1016/j.molcel.2024.06.025 * Korb, E., Herre, M., Zucker-Scharff, I., Gresack, J., Allis, C. D., & Darnell, R. B. (2017). Excess Translation of Epigenetic Regulators Contributes to Fragile X Syndrome and Is Alleviated by Brd4 Inhibition. Cell, 170(6), 1209–1223.e20. https://doi.org/10.1016/j.cell.2017.07.033 * Kee, J., Thudium, S., Renner, D. M., Glastad, K., Palozola, K., Zhang, Z., Li, Y., Lan, Y., Cesare, J., Poleshko, A., Kiseleva, A. A., Truitt, R., Cardenas-Diaz, F. L., Zhang, X., Xie, X., Kotton, D. N., Alysandratos, K. D., Epstein, J. A., Shi, P. Y., Yang, W., … Korb, E. (2022). SARS-CoV-2 disrupts host epigenetic regulation via histone mimicry. Nature, 610(7931), 381–388. https://doi.org/10.1038/s41586-022-05282-z * Feierman, E. R., Paranjapye, A., Su, S., Qiu, Q., Wu, H., & Korb, E. (2024). Histone variant H2BE controls activity-dependent gene expression and homeostatic scaling. bioRxiv : the preprint server for biology*, 2024.11.01.620920. https://doi.org/10.1101/2024.11.01.620920
Related Episodes* Neuroepigenetic Mechanisms and Primate Epigenome Evolution (Boyan Bonev) * DNA Methylation Alterations in Neurodegenerative Diseases (Paula Desplats) * The Role of Histone Dopaminylation and Serotinylation in Neuronal Plasticity (Ian Maze)
Contact* Epigenetics Podcast on Mastodon * Epigenetics Podcast on Bluesky * Dr. Stefan Dillinger on LinkedIn * Active Motif on LinkedIn * Active Motif on Bluesky * Email: podcast@activemotif.com
In this episode of the Epigenetics Podcast, we talked with Dr. Joseph Ecker from the Salk Institute about his work on high-resolution genome-wide mapping technologies, specifically how the regulation of gene expression is influenced by DNA methylation, chromatin accessibility, and non-coding RNAs across various cell types and developmental stages.
During our conversation, we delve into Dr. Ecker's contributions to the characterization of the genome of Arabidopsis thaliana, a project pivotal in the plant genomics field, where he collaborated on the early sequencing efforts that dramatically outpaced expectations. He highlights the technological advancements that enabled such efficient sequencing and how this foundational work opened new avenues for exploring transcriptional activity.
We also discuss Dr. Ecker’s pivotal work on the comprehensive DNA methylation map of Arabidopsis, which he developed in collaboration with other researchers. This groundbreaking study established the links between methylation patterns and gene expression, paving the way for further research into how these epigenetic marks influence over gene regulation. He elaborates on the significance of transitioning from traditional methods to more sophisticated techniques, such as RNA-seq, and the lessons learned from sequencing projects that have since been applied to human biology.
Dr. Ecker's transition to studying human cells is further explored as he discusses the profiling of DNA methylation in induced pluripotent stem cells (iPSCs), revealing how epigenetic memory can influence cellular differentiation and development. He underscores the importance of understanding these methylation patterns, particularly as they relate to conditions like Alzheimer's disease and stem cell biology, where he examines potential applications of his findings in medical research.
As our conversation progresses, we touch upon Dr. Ecker's ongoing projects that utilize advanced multi-omic techniques to investigate the epigenomes of the human brain, focusing on how DNA methylation and gene expression change with age and in the context of neurodegenerative diseases. He details the collaboration efforts with various consortia aimed at cataloging gene regulatory networks and understanding the complex interactions that take place within the brain throughout different life stages.
References* Mozo T, Dewar K, Dunn P, Ecker JR, Fischer S, Kloska S, Lehrach H, Marra M, Martienssen R, Meier-Ewert S, Altmann T. A complete BAC-based physical map of the Arabidopsis thaliana genome. Nat Genet. 1999 Jul;22(3):271-5. doi: 10.1038/10334. PMID: 10391215. * Zhang X, Yazaki J, Sundaresan A, Cokus S, Chan SW, Chen H, Henderson IR, Shinn P, Pellegrini M, Jacobsen SE, Ecker JR. Genome-wide high-resolution mapping and functional analysis of DNA methylation in arabidopsis. Cell. 2006 Sep 22;126(6):1189-201. doi: 10.1016/j.cell.2006.08.003. Epub 2006 Aug 31. PMID: 16949657. * Lister R, O'Malley RC, Tonti-Filippini J, Gregory BD, Berry CC, Millar AH, Ecker JR. Highly integrated single-base resolution maps of the epigenome in Arabidopsis. Cell. 2008 May 2;133(3):523-36. doi: 10.1016/j.cell.2008.03.029. PMID: 18423832; PMCID: PMC2723732. * Lister R, Pelizzola M, Dowen RH, Hawkins RD, Hon G, Tonti-Filippini J, Nery JR, Lee L, Ye Z, Ngo QM, Edsall L, Antosiewicz-Bourget J, Stewart R, Ruotti V, Millar AH, Thomson JA, Ren B, Ecker JR. Human DNA methylomes at base resolution show widespread epigenomic differences. Nature. 2009 Nov 19;462(7271):315-22. doi: 10.1038/nature08514. Epub 2009 Oct 14. PMID: 19829295; PMCID: PMC2857523. * Lister R, Pelizzola M, Kida YS, Hawkins RD, Nery JR, Hon G, Antosiewicz-Bourget J, O'Malley R, Castanon R, Klugman S, Downes M, Yu R, Stewart R, Ren B, Thomson JA, Evans RM, Ecker JR. Hotspots of aberrant epigenomic reprogramming in human induced pluripotent stem cells. Nature. 2011 Mar 3;471(7336):68-73. doi: 10.1038/nature09798. Epub 2011 Feb 2. Erratum in: Nature. 2014 Oct 2;514(7520):126. PMID: 21289626; PMCID: PMC3100360.
Related Episodes* Epigenetic Reprogramming During Mammalian Development (Wolf Reik) * Single Cell Epigenomics in Neuronal Development (Tim Petros)
Contact* Epigenetics Podcast on Mastodon * Epigenetics Podcast on Bluesky * Dr. Stefan Dillinger on LinkedIn * Active Motif on LinkedIn * Active Motif on Bluesky * Email: podcast@activemotif.com
In this episode of the Epigenetics Podcast, we talked with Sarah Teichmann from the University of Cambridge about the Human Cell Atlas.
In the Interview we explore Sarah Teichmann's impressive career trajectory, covering her current role as Chair of Stem Cell Medicine at the Cambridge Stem Cell Institute and Vice President of Translational Research at GlaxoSmithKline. Professor Teichmann explains her unique dual appointments, a rare arrangement that allows her to bridge academia and industry effectively.
As the conversation shifts focus to computational biology, she takes us on a historical journey from her PhD work at the MRC Laboratory of Molecular Biology to the present advancements driven by next-generation sequencing and artificial intelligence methods. Professor Teichmann emphasizes that the landscape of biological research has evolved significantly, particularly in the realm of data-driven methodologies.
The conversation then transitions seamlessly into her pivotal role in advancing single-cell genomics, where she discusses the motivation behind using single-cell RNA sequencing methods in her research on T cells. This technique offered unmatched insights compared to bulk sequencing techniques, allowing for a more detailed understanding of cell states and their complex interactions within tissues.
A highlight of the episode is Professor Teichmann's insights on the Human Cell Atlas project, which she co-founded in 2017. She elaborates on the ambitious vision to map all human cells, likening the endeavor to the Human Genome Project. Through the atlas, researchers aim to create a detailed reference map that facilitates a deeper understanding of human health and disease. Professor Teichmann shares the collaborative efforts that led to its inception and the importance of international cooperation in scientific research.
The discussion culminates with an exploration of the biggest scientific findings thus far from the Human Cell Atlas. Among the revelations, she notes the astounding complexity and diversity of cell types identified, particularly within the immune system, and the unexpected locations of certain cell types during human development. She also highlights significant discoveries related to COVID-19, demonstrating the immediate real-world impact of their work.
References https://www.humancellatlas.org * The Human Cell Atlas: towards a first draft atlas * Kock, K. H., Tan, L. M., Han, K. Y., Ando, Y., Jevapatarakul, D., Chatterjee, A., Lin, Q. X. X., Buyamin, E. V., Sonthalia, R., Rajagopalan, D., Tomofuji, Y., Sankaran, S., Park, M. S., Abe, M., Chantaraamporn, J., Furukawa, S., Ghosh, S., Inoue, G., Kojima, M., Kouno, T., … Prabhakar, S. (2025). Asian diversity in human immune cells. Cell, 188*(8), 2288–2306.e24. https://doi.org/10.1016/j.cell.2025.02.017
Related Episodes* The Discovery of Genomic Imprinting (Azim Surani)
Contact* Epigenetics Podcast on Mastodon * Epigenetics Podcast on Bluesky * Dr. Stefan Dillinger on LinkedIn * Active Motif on LinkedIn * Active Motif on Bluesky * Email: podcast@activemotif.com
In this episode, Professor Asim Surani, shares how his extensive research has significantly advanced the understanding of how the mammalian germline is specified, the mechanisms governing epigenetic reprogramming, and the critical conditions that maintain genomic integrity during early development. The discussion, led by Dr. Stefan Dillinger, provides an overview of Surani's journey into biology, the evolution of his research interests, and the pivotal discoveries that have shaped the field of epigenetics.
Dr. Surani discusses the groundbreaking experiment he co-conducted in 1984 that led to the discovery of genomic imprinting. Initially a student involved in in vitro fertilization at Cambridge, he became intrigued by the implications of parthenogenesis in mammals. Challenging the prevailing cytoplasmic theory of development, Surani and his collaborators demonstrated that normal mammalian development requires contributions from both parental genomes, leading to the introduction of the concept of genomic imprinting—a term Surani defended to describe the phenomenon that he and his team observed.
Surani's research then evolved toward understanding the mechanisms of genomic imprinting, particularly the role of DNA methylation. Throughout the interview, he details specific experiments that elucidated how genes could exhibit imprinted expression depending on the parental lineage, highlighting the importance of epigenetic factors in gene regulation. The revelation that DNA methylation marks were responsible for imprinting solidified the connection between genetic information and epigenetic influence in development.
The conversation dives deeper into the mechanisms involved in germline specification and epigenetic reprogramming. Surani explains his transition into studying mammalian germline development and the intricacies of primordial germ cell specification. Working with his team, he utilized single-cell approaches to investigate gene expression profiles specific to germ cells, identifying critical factors like PRDM1 and PRDM14 that repress somatic gene programs while initiating germline-specific pathways. This work underscored the complex interplay of genetic and epigenetic factors that govern the development of germ cells.
Another focus of the interview is the comparison of epigenetic resetting between mouse and human germlines. Surani addresses key differences in the timing and mechanisms of epigenetic reprogramming in humans, particularly the involvement of specific factors such as SOX17, which emerged as a crucial player in human germline specification, contrary to his earlier expectations. The discussion also highlights the technical challenges researchers face when studying human embryos due to ethical constraints, driving innovation in model systems such as stem cells to explore germline development.
References* Surani MA, Barton SC, Norris ML. Development of reconstituted mouse eggs suggests imprinting of the genome during gametogenesis. Nature. 1984 Apr 5-11;308(5959):548-50. doi: 10.1038/308548a0. PMID: 6709062. * Surani MA, Barton SC, Norris ML. Nuclear transplantation in the mouse: heritable differences between parental genomes after activation of the embryonic genome. Cell. 1986 Apr 11;45(1):127-36. doi: 10.1016/0092-8674(86)90544-1. PMID: 3955655. * Ohinata Y, Payer B, O'Carroll D, Ancelin K, Ono Y, Sano M, Barton SC, Obukhanych T, Nussenzweig M, Tarakhovsky A, Saitou M, Surani MA. Blimp1 is a critical determinant of the germ cell lineage in mice. Nature. 2005 Jul 14;436(7048):207-13. doi: 10.1038/nature03813. Epub 2005 Jun 5. PMID: 15937476. * Hajkova P, Ancelin K, Waldmann T, Lacoste N, Lange UC, Cesari F, Lee C, Almouzni G, Schneider R, Surani MA. Chromatin dynamics during epigenetic reprogramming in the mouse germ line. Nature. 2008 Apr 17;452(7189):877-81. doi: 10.1038/nature06714. Epub 2008 Mar 19. PMID: 18354397; PMCID: PMC3847605.
Related Episodes* Epigenetic Reprogramming During Mammalian Development (Wolf Reik) * Epigenetic and Metabolic Regulation of Early Development (Jan Żylicz) * Epigenetic Mechanisms in Genome Regulation and Developmental Programming (James Hackett) * Epigenetic Mechanisms of Mammalian Germ Cell Development (Mitinori Saitou) * Exploring DNA Methylation and TET Enzymes in Early Development (Petra Hajkova)
Contact* Epigenetics Podcast on Mastodon * Epigenetics Podcast on Bluesky * Dr. Stefan Dillinger on LinkedIn * Active Motif on LinkedIn * Active Motif on Bluesky * Email: podcast@activemotif.com
In this episode of the Epigenetics Podcast, we talked with Petra Hajkova from the MRC Laboratory of Medical Sciences about her work on epigenetics research on mammalian development, highlighting DNA methylation, histone modifications, and TET enzymes, along with her journey in molecular genetics and future research on epigenetic maintenance.
Dr. Hajkova's early work focused on DNA methylation and resulted in innovative collaboration that allowed her to develop bisulfide sequencing techniques. We discuss her transition to the UK, where she began working in Azim Surani's lab at the University of Cambridge. Dr. Hajkova describes the excitement of researching chromatin dynamics in the mouse germline, leading to significant findings published in Nature. Her story highlights the intense yet rewarding nature of postdoctoral research as she navigated the complexities of working with embryos for the first time.
As her research progressed, Dr. Hajkova established her own lab at the MRC London Institute of Medical Sciences, where she became a professor in 2017. We delve into her investigations on the differences between embryonic stem cells and embryonic germ cells regarding their distinct developmental origins. Dr. Hajkova outlines the challenges she faced in understanding the mechanisms behind global DNA demethylation in germline cells and the role of hydroxymethylation during early development.
The discussion further covers her exciting findings regarding the specific functions of TET enzymes and their regulatory roles in maintaining epigenetic states. We explore her recent research published in Nature, which provides insights into the transition from primordial germ cells to gonocytes, emphasizing the significance of various epigenetic mechanisms in germline development.
References* Hajkova P, Ancelin K, Waldmann T, Lacoste N, Lange UC, Cesari F, Lee C, Almouzni G, Schneider R, Surani MA. Chromatin dynamics during epigenetic reprogramming in the mouse germ line. Nature. 2008 Apr 17;452(7189):877-81. doi: 10.1038/nature06714. Epub 2008 Mar 19. PMID: 18354397; PMCID: PMC3847605. * Hajkova P, Jeffries SJ, Lee C, Miller N, Jackson SP, Surani MA. Genome-wide reprogramming in the mouse germ line entails the base excision repair pathway. Science. 2010 Jul 2;329(5987):78-82. doi: 10.1126/science.1187945. PMID: 20595612; PMCID: PMC3863715. * Hill PWS, Leitch HG, Requena CE, Sun Z, Amouroux R, Roman-Trufero M, Borkowska M, Terragni J, Vaisvila R, Linnett S, Bagci H, Dharmalingham G, Haberle V, Lenhard B, Zheng Y, Pradhan S, Hajkova P. Epigenetic reprogramming enables the transition from primordial germ cell to gonocyte. Nature. 2018 Mar 15;555(7696):392-396. doi: 10.1038/nature25964. Epub 2018 Mar 7. PMID: 29513657; PMCID: PMC5856367. * Huang TC, Wang YF, Vazquez-Ferrer E, Theofel I, Requena CE, Hanna CW, Kelsey G, Hajkova P. Sex-specific chromatin remodelling safeguards transcription in germ cells. Nature. 2021 Dec;600(7890):737-742. doi: 10.1038/s41586-021-04208-5. Epub 2021 Dec 8. PMID: 34880491.
Related Episodes* Epigenetic Mechanisms of Mammalian Germ Cell Development (Mitinori Saitou) * Epigenetic Reprogramming During Mammalian Development (Wolf Reik) * DNA Methylation and Mammalian Development (Déborah Bourc'his)
Contact* Epigenetics Podcast on Mastodon * Epigenetics Podcast on Bluesky * Dr. Stefan Dillinger on LinkedIn * Active Motif on LinkedIn * Active Motif on Bluesky * Email: podcast@activemotif.com
In this episode of the Epigenetics Podcast, we talked with Ani Deshpande from Sanford Burnham Prebys about his work on epigenetic regulation and developing small molecules through high throughput screens for AML.
Throughout our discussion, we delve into Dr. Despande's journey into the field of biology and science, tracing his evolution from a literature enthusiast in Mumbai to a dedicated cancer researcher. He reflects on his formative experiences during his PhD at Ludwig Maximilian University in Munich, where she developed murine models for refractory acute myeloid leukemia (AML). We examine these models' contributions to therapeutic discovery and understanding the intricate mechanisms underscoring AML's complexities.
Transitioning to his postdoctoral work at Scott Armstrong's lab in Boston, Dr. Despande shares his insights on the importance of epigenetic regulators, such as DOT1L, in leukemias, and how they can serve as strategic therapeutic targets. His ambitious pursuit of translational research is further highlighted through his efforts in developing a conditional knockout mouse model and his collaborative work utilizing CRISPR technology to refine our understanding of epigenetic regulation in cancer pathogenesis.
Moreover, we engage in a conversation about the challenges and opportunities that arise when establishing his lab at Sanford Burnham Prebys. Dr. Despande candidly discusses the delicate balance between pursuing topics of genuine interest versus adhering to grant fundability, underlining the tension researchers face in the current scientific landscape. His emphasis on the critical need for innovation within lab settings serves as a motivational call for emerging scientists to venture beyond the established templates that often inhibit groundbreaking discoveries.
We conclude our dialogue with an exploration of his recent projects, which involve targeting specific epigenetic modifiers and how his lab’s findings can contribute to greater understanding and potential treatments for not only AML but also other pediatric cancers driven by gene fusions. Dr. Despande's insights into the integration of modern technologies, such as CRISPR libraries, exemplify his commitment to pushing the boundaries of cancer research.
In addition to discussing his scientific contributions, we touch upon Dr. Despande's foray into podcasting (The Discovery Dialogues), shedding light on his motivation to bridge the communication gap between scientists and the broader public. He articulates his desire to demystify scientific discoveries and promote awareness about the intricate journey of research that lays the groundwork for medical advancements. This multidimensional discussion not only highlights his scientific achievements but also emphasizes the importance of effective science communication in fostering public understanding and appreciation of research.
References* Deshpande AJ, Cusan M, Rawat VP, Reuter H, Krause A, Pott C, Quintanilla-Martinez L, Kakadia P, Kuchenbauer F, Ahmed F, Delabesse E, Hahn M, Lichter P, Kneba M, Hiddemann W, Macintyre E, Mecucci C, Ludwig WD, Humphries RK, Bohlander SK, Feuring-Buske M, Buske C. Acute myeloid leukemia is propagated by a leukemic stem cell with lymphoid characteristics in a mouse model of CALM/AF10-positive leukemia. Cancer Cell. 2006 Nov;10(5):363-74. doi: 10.1016/j.ccr.2006.08.023. PMID: 17097559. * Deshpande AJ, Deshpande A, Sinha AU, Chen L, Chang J, Cihan A, Fazio M, Chen CW, Zhu N, Koche R, Dzhekieva L, Ibáñez G, Dias S, Banka D, Krivtsov A, Luo M, Roeder RG, Bradner JE, Bernt KM, Armstrong SA. AF10 regulates progressive H3K79 methylation and HOX gene expression in diverse AML subtypes. Cancer Cell. 2014 Dec 8;26(6):896-908. doi: 10.1016/j.ccell.2014.10.009. Epub 2014 Nov 20. PMID: 25464900; PMCID: PMC4291116. * Sinha S, Barbosa K, Cheng K, Leiserson MDM, Jain P, Deshpande A, Wilson DM 3rd, Ryan BM, Luo J, Ronai ZA, Lee JS, Deshpande AJ, Ruppin E. A systematic genome-wide mapping of oncogenic mutation selection during CRISPR-Cas9 genome editing. Nat Commun. 2021 Nov 11;12(1):6512. doi: 10.1038/s41467-021-26788-6. Erratum in: Nat Commun. 2022 May 16;13(1):2828. doi: 10.1038/s41467-022-30475-5. PMID: 34764240; PMCID: PMC8586238.
Related Episodes* Targeting COMPASS to Cure Childhood Leukemia (Ali Shilatifard) * The Menin-MLL Complex and Small Molecule Inhibitors (Yadira Soto-Feliciano) * MLL Proteins in Mixed-Lineage Leukemia (Yali Dou)
Contact* Epigenetics Podcast on Mastodon * Epigenetics Podcast on Bluesky * Dr. Stefan Dillinger on LinkedIn * Active Motif on LinkedIn * Active Motif on Bluesky * Email: podcast@activemotif.com
In this episode Dr. Raffaele Teperino shares insights from his ongoing research focused on developmental programming, particularly how paternal health before conception influences not only offspring health but also maternal health outcomes. As we trace his academic journey from studying biotechnology and pharmacology to leading his own lab, Dr. Teperino reflects on his early fascination with medicine, the pivotal experiences that shaped his career, and the integration of epigenetics into understanding metabolic diseases.
We discuss the nuances of epigenetics—going beyond simple chromatin biology to examine its wider implications on phenotypic variation. Dr. Teperino emphasizes his approach of modeling relevant physiological phenomena in the lab to better understand the underlying mechanisms driving conditions like obesity and metabolic disruption. A particular focus is placed on his experiences during his postdoctoral years, where he investigated the developmental pathways of hedgehog signaling and its metabolic implications in adipogenesis.
Our talk shifts towards the practical implications of his research, highlighting recent investigations into how circadian rhythms and paternal lifestyles influence offspring health. Dr. Teperino reveals his findings on how disturbances in circadian rhythms can lead to intergenerational health issues, showcasing the surprising effects observed in offspring of fathers experiencing circadian misalignment. We delve into the significance of seminal fluid as a potential medium for intergenerational transfer of stress responses, examining the role of stress hormones and their impacts on fetal development.
As we explore a fascinating recent study highlighting the impact of paternal diets on future generations, Dr. Teperino underscores the importance of understanding the shorter exposure periods sufficient to trigger these health changes. He presents data that links paternal obesity and preconception health to an increased risk of obesity and insulin resistance in children, challenging traditional narratives around maternal responsibility for offspring health.
References* Darr J, Tomar A, Lassi M, Gerlini R, Berti L, Hering A, Scheid F, Hrabě de Angelis M, Witting M, Teperino R. iTAG-RNA Isolates Cell-Specific Transcriptional Responses to Environmental Stimuli and Identifies an RNA-Based Endocrine Axis. Cell Rep. 2020 Mar 3;30(9):3183-3194.e4. doi: 10.1016/j.celrep.2020.02.020. PMID: 32130917. * Lassi M, Tomar A, Comas-Armangué G, Vogtmann R, Dijkstra DJ, Corujo D, Gerlini R, Darr J, Scheid F, Rozman J, Aguilar-Pimentel A, Koren O, Buschbeck M, Fuchs H, Marschall S, Gailus-Durner V, Hrabe de Angelis M, Plösch T, Gellhaus A, Teperino R. Disruption of paternal circadian rhythm affects metabolic health in male offspring via nongerm cell factors. Sci Adv. 2021 May 26;7(22):eabg6424. doi: 10.1126/sciadv.abg6424. PMID: 34039610; PMCID: PMC8153725. * Tomar A, Gomez-Velazquez M, Gerlini R, Comas-Armangué G, Makharadze L, Kolbe T, Boersma A, Dahlhoff M, Burgstaller JP, Lassi M, Darr J, Toppari J, Virtanen H, Kühnapfel A, Scholz M, Landgraf K, Kiess W, Vogel M, Gailus-Durner V, Fuchs H, Marschall S, Hrabě de Angelis M, Kotaja N, Körner A, Teperino R. Epigenetic inheritance of diet-induced and sperm-borne mitochondrial RNAs. Nature. 2024 Jun;630(8017):720-727. doi: 10.1038/s41586-024-07472-3. Epub 2024 Jun 5. PMID: 38839949; PMCID: PMC11186758.
Related Episodes* The Impact of Paternal Diet on Offspring Metabolism (Upasna Sharma) * Transgenerational Inheritance and Evolution of Epimutations (Peter Sarkies) * The Role of Small RNAs in Transgenerational Inheritance in C. elegans (Oded Rechavi)
Contact* Epigenetics Podcast on Mastodon * Epigenetics Podcast on Bluesky * Dr. Stefan Dillinger on LinkedIn * Active Motif on LinkedIn * Active Motif on Bluesky * Email: podcast@activemotif.com
In this episode of the Epigenetics Podcast, we talked with Dr. Frank Johannes from the Technical University of Munich in Freising about his work on evolutionary clocks and epigenetic inheritance in plants.
In this episode we discuss Dr. Johannes pursuits in understanding how heritable epigenetic variations, particularly through DNA methylation, affect phenotypic diversity in plants. He shared insights about groundbreaking research initiatives he has led, including one of the first population epigenetic studies in plants that effectively linked heritable DNA methylation changes to critical traits like flowering time and root length. This work underscored the importance of epigenetic factors that extend beyond traditional genetic sequences, illustrating a significant shift in how we comprehend inheritance and trait variation in organisms.
As we dug deeper into the science, we examined Dr. Johannes's innovative approaches to studying chromatin-based mechanisms of genome regulation, allowing for a nuanced understanding of epigenetic inheritance. His lab’s extensive phenotyping of Arabidopsis plants highlighted how inducing heritable variations in DNA methylation could lead to significant trait outcomes – results that have substantial implications for agriculture and understanding complex characteristics across generations.
The dialogue continued to unravel the dynamics between forward and backward epimutations, delving into their heritable nature and their rapid accumulation compared to traditional genetic mutations. Dr. Johannes overturned conventional understanding by presenting epigenetic processes that are not as static as once thought, providing compelling evidence that these spontaneous changes could inform evolutionary clocks; a concept that offers new avenues for studying the relationships between species over relatively short timeframes.
Moreover, we discussed the exciting concept of epigenetic clocks, which play a role in assessing the age of various species, including trees. The potential applications for such clocks in environmental management and the assessment of tree vitality further illuminated the practical impacts of Dr. Johannes's research. These insights also pave the way for sophisticated non-invasive methods of understanding plant biology, which can revolutionize forest management practices in the face of climate change and other ecological pressures.
References* Colomé-Tatché M, Cortijo S, Wardenaar R, Morgado L, Lahouze B, Sarazin A, Etcheverry M, Martin A, Feng S, Duvernois-Berthet E, Labadie K, Wincker P, Jacobsen SE, Jansen RC, Colot V, Johannes F. Features of the Arabidopsis recombination landscape resulting from the combined loss of sequence variation and DNA methylation. Proc Natl Acad Sci U S A. 2012 Oct 2;109(40):16240-5. doi: 10.1073/pnas.1212955109. Epub 2012 Sep 17. PMID: 22988127; PMCID: PMC3479620. * Cortijo S, Wardenaar R, Colomé-Tatché M, Gilly A, Etcheverry M, Labadie K, Caillieux E, Hospital F, Aury JM, Wincker P, Roudier F, Jansen RC, Colot V, Johannes F. Mapping the epigenetic basis of complex traits. Science. 2014 Mar 7;343(6175):1145-8. doi: 10.1126/science.1248127. Epub 2014 Feb 6. PMID: 24505129. * van der Graaf A, Wardenaar R, Neumann DA, Taudt A, Shaw RG, Jansen RC, Schmitz RJ, Colomé-Tatché M, Johannes F. Rate, spectrum, and evolutionary dynamics of spontaneous epimutations. Proc Natl Acad Sci U S A. 2015 May 26;112(21):6676-81. doi: 10.1073/pnas.1424254112. Epub 2015 May 11. PMID: 25964364; PMCID: PMC4450394. * Yao N, Zhang Z, Yu L, Hazarika R, Yu C, Jang H, Smith LM, Ton J, Liu L, Stachowicz JJ, Reusch TBH, Schmitz RJ, Johannes F. An evolutionary epigenetic clock in plants. Science. 2023 Sep 29;381(6665):1440-1445. doi: 10.1126/science.adh9443. Epub 2023 Sep 28. PMID: 37769069.
Related Episodes* Transgenerational Inheritance and Epigenetic Imprinting in Plants (Mary Gehring) * Epigenetic Clocks and Biomarkers of Ageing (Morgan Levine)
Contact* Epigenetics Podcast on Mastodon * Epigenetics Podcast on Bluesky * Dr. Stefan Dillinger on LinkedIn * Active Motif on LinkedIn * Active Motif on Bluesky * Email: podcast@activemotif.com
In this episode of the Epigenetics Podcast, we talked with Boyan Bonev from the HelmholtzZetrum in Munich about his work on neuroepigenetics, focusing on gene regulation, chromatin architecture, and primate epigenome evolution,
This Episode focuses on Dr. Bonev’s recent research, particularly focusing on how chromatin architecture and gene regulation influence neural cell identity and function. He discusses his work investigating transcriptional activity in relation to chromatin insulation, highlighting a critical finding that induced expression of genes does not necessarily lead to chromatin insulation—a point that complicates prior assumptions about the relationship between gene expression and chromatin organization. This study aimed to determine the causal versus correlative aspects of chromatin architecture in brain development and links it to developmental processes and neurodevelopmental disorders.
Building on his findings in gene regulation, Dr. Bonev elaborates on a significant study he conducted in his own lab, where he mapped the regulatory landscape of neural differentiation in the mouse neocortex. Here, he employed cutting-edge single-cell sequencing methodologies to analyze intricate gene and enhancer interactions, revealing that selective enhancer-promoter interactions are primarily cell-type specific. This nuanced understanding aids in deciphering the complexities associated with gene expression as it relates to neural stem cells and differentiated neurons, emphasizing the importance of single-cell analyses over bulk sequencing methods.
Moreover, Dr. Bonev reveals a novel methodology developed in his lab that allows for the simultaneous assessment of spatial genome organization, chromatin accessibility, and DNA methylation at high resolution. This advancement not only reduces costs but also enhances the potential to correlate higher-dimensional genomic data with specific biological questions, fostering a more integrative approach to understanding genetic regulation.
The discussion then shifts focus towards Dr. Bonev's recent project profiling primate epigenome evolution, where he investigated the 3D genome organization, chromatin accessibility, and gene expression among iPSCs and neural stem cells from various species, including humans, chimpanzees, gorillas, and macaques. In this research, he identifies trends related to transcription factor evolution and chromatin modifications across species. The insights gleaned from this work underscore the evolutionary significance of structural variations in the 3D genome, pointing to a possible link between chromatin dynamics and the evolutionary development of the primate brain.
References Bonev B, Mendelson Cohen N, Szabo Q, Fritsch L, Papadopoulos GL, Lubling Y, Xu X, Lv X, Hugnot JP, Tanay A, Cavalli G. Multiscale 3D Genome Rewiring during Mouse Neural Development. Cell. 2017 Oct 19;171(3):557-572.e24. doi: https://doi.org/10.1016/j.cell.2017.09.043. PMID: 29053968; PMCID: PMC5651218. * Noack, F., Vangelisti, S., Raffl, G. et al. Multimodal profiling of the transcriptional regulatory landscape of the developing mouse cortex identifies Neurog2 as a key epigenome remodeler. Nat Neurosci* 25, 154–167 (2022). https://doi.org/10.1038/s41593-021-01002-4 * Noack F, Vangelisti S, Ditzer N, Chong F, Albert M, Bonev B. Joint epigenome profiling reveals cell-type-specific gene regulatory programmes in human cortical organoids. Nat Cell Biol. 2023 Dec;25(12):1873-1883. doi: 10.1038/s41556-023-01296-5. Epub 2023 Nov 23. PMID: 37996647; PMCID: PMC10709149.
Related Episodes* Characterization of Epigenetic States in the Oligodendrocyte Lineage (Gonçalo Castelo-Branco) * Polycomb Proteins, Gene Regulation, and Genome Organization in Drosophila (Giacomo Cavalli) * The Effect of lncRNAs on Chromatin and Gene Regulation (John Rinn)
Contact* Epigenetics Podcast on Mastodon * Epigenetics Podcast on Bluesky * Dr. Stefan Dillinger on LinkedIn * Active Motif on LinkedIn * Active Motif on Bluesky * Email: podcast@activemotif.com
In this episode of the Epigenetics Podcast, we talked with Dr. Eva Hörmanseder from the HelmholtzZentrum in Munich about her work on epigenetic mechanisms in cellular memory and gene regulation.
In this episode, we delve into the fascinating world of cellular memory and gene regulation with Dr. Eva Hermanns-Eder from the Helmholtz Zentrum in Munich. Her research centers on how cells maintain their identity through the process of mitotic divisions, which is crucial for understanding both development and various diseases. We explore the role of chromatin dynamics and epigenetic modifications in switching genes on and off over time, which has significant implications for fields like cancer biology and regenerative medicine.
The discussion starts with Dr. Hörmanseder's recent studies on epigenetic memories, particularly focusing on the concept of transcriptional memory in nuclear transfer embryos. She explains her work with H3K4 trimethylation, a crucial epigenetic mark associated with active transcription states, detailing experiments that demonstrate the significance of this mark in the context of gene expression during reprogramming. She elaborates on her findings regarding how active genes can remain in a state of transcriptional memory and the implications of such persistence for cellular identity.
We also dive into Dr. Hörmanseder's exploration of how transcription factors and chromatin modifications shape the differentiation success of reprogrammed cells. Through her research, she uncovers that different cell types exhibit varying degrees of plasticity and memory retention, which can lead to disparities in successful differentiation. Her innovative use of single-cell sequencing technology reveals surprising insights into the dynamics of cellular reprogramming, especially when comparing reprogrammed cells to their fertilized counterparts.
References Hörmanseder E, Simeone A, Allen GE, Bradshaw CR, Figlmüller M, Gurdon J, Jullien J. H3K4 Methylation-Dependent Memory of Somatic Cell Identity Inhibits Reprogramming and Development of Nuclear Transfer Embryos. Cell Stem Cell. 2017 Jul 6;21(1):135-143.e6. doi: 10.1016/j.stem.2017.03.003. Epub 2017 Mar 30. PMID: 28366589; PMCID: PMC5505866. * Zikmund, T., Fiorentino, J., Penfold, C., Stock, M., Shpudeiko, P., Agarwal, G., Langfeld, L., Petrova, K., Peshkin, L., Hamperl, S., Scialdone, A., & Hoermanseder, E. (2025). Differentiation success of reprogrammed cells is heterogeneous in vivo and modulated by somatic cell identity memory. Stem Cell Reports*, 102447. https://doi.org/10.1016/j.stemcr.2025.102447
Related Episodes* H3K4me3, SET Proteins, Isw1, and their Role in Transcription (Jane Mellor) * DNA Replication, Transcription and R-loops (Stephan Hamperl) * Inheritance of Transcriptional Memory by Mitotic Bookmarking (Sheila Teves)
Contact* Epigenetics Podcast on Mastodon * Epigenetics Podcast on Bluesky * Dr. Stefan Dillinger on LinkedIn * Active Motif on LinkedIn * Active Motif on Bluesky * Email: podcast@activemotif.com
In this episode of the Epigenetics Podcast, we talked with Viviana Risca from Rockefeller University about her work on RICC-Seq and how it's used to probe DNA-DNA contacts in intact or fixed cells using ionizing radiation.
This Interview covers Dr. Viviana Risca's cutting-edge methodologies, such as RICC-seq, which enables high-resolution analysis of chromatin structures without traditional cross-linking biases. We engage in a detailed discussion about how different techniques, such as RICC-seq and Micro-C, complement each other to provide robust insights into nucleosome interactions and chromatin dynamics. Dr. Risca articulates the challenges and innovations within her lab as it navigates through the complexities of chromatin mapping.
The episode takes an exciting turn toward traversing the landscape of her future research directions, particularly studying the role of linker histones and other chromatin architectural proteins in regulating gene expression. Dr. Risca emphasizes the importance of understanding chromatin's mechanical properties and how these influence cellular processes like transcriptional regulation, DNA replication, and cellular responses to damage.
We also explore her collaborative work that bridges the gap between basic research and clinical applications, particularly in cancer therapy. Dr. Risca shares insights into her investigations into how chromatin dynamics change during cell cycle arrest and their implications for cancer therapy resistance. Our discussion culminates in her reflections on the definition of epigenetics, framing it as the exploration of how cellular mechanisms encode and process information.
References Risca VI, Denny SK, Straight AF, Greenleaf WJ. Variable chromatin structure revealed by in situ spatially correlated DNA cleavage mapping. Nature. 2017 Jan 12;541(7636):237-241. doi: 10.1038/nature20781. Epub 2016 Dec 26. PMID: 28024297; PMCID: PMC5526328. * Soroczynski J, Anderson LJ, Yeung JL, Rendleman JM, Oren DA, Konishi HA, Risca VI. OpenTn5: Open-Source Resource for Robust and Scalable Tn5 Transposase Purification and Characterization. bioRxiv [Preprint]. 2024 Jul 13:2024.07.11.602973. doi: 10.1101/2024.07.11.602973. PMID: 39026714; PMCID: PMC11257509. * Prescott, N. A., Biaco, T., Mansisidor, A., Bram, Y., Rendleman, J., Faulkner, S. C., Lemmon, A. A., Lim, C., Tiersky, R., Salataj, E., Garcia-Martinez, L., Borges, R. L., Morey, L., Hamard, P.-J., Koche, R. P., Risca, V. I., Schwartz, R. E., & David, Y. (2025). A nucleosome switch primes hepatitis B virus infection. Cell*, S0092867425001023. https://doi.org/10.1016/j.cell.2025.01.033
Related Episodes* Hi-C and Three-Dimensional Genome Sequencing (Erez Lieberman Aiden) * Split-Pool Recognition of Interactions by Tag Extension (SPRITE) (Mitch Guttman) * Effects of Non-Enzymatic Covalent Histone Modifications on Chromatin (Yael David)
Contact* Epigenetics Podcast on Mastodon * Epigenetics Podcast on Bluesky * Dr. Stefan Dillinger on LinkedIn * Active Motif on LinkedIn * Active Motif on Bluesky * Email: podcast@activemotif.com
In this episode of the Epigenetics Podcast, we talked with Geeta Narlikar from UCSF about her work on chromatin remodeling, Heterochromatin Protein 1, and the molecular mechanisms that influence the genome.
The conversation starts with a pivotal paper from the early days of Dr. Narlikars research career, titled "Distinct Strategies to Make Nucleosomal DNA Accessible," focused on two ATP-dependent remodelers, BRG1 and SNF2H. Here, she notes that while both enzymes operate similarly, they generate different outputs and play distinct biological roles within the cell. The research revealed that BRG1 is more aggressive in altering nucleosome configuration, aligning with its role in transcription activation, while SNF2H showed a more refined approach in the formation of heterochromatin.
Transitioning to her work at UCSF, she emphasized the importance of collaboration and mentoring within a research group. Her focus then shifted towards the ACF ATP-dependent chromatin assembly factor, hypothesizing how ACF measures nucleosome distance—an inquiry that led to exciting insights regarding dynamic enzyme behavior. This includes findings that ACF operates not through a static ruler mechanism but rather through a kinetic mechanism, thus continuously adjusting nucleosome positioning based on DNA length during chromatin assembly.
Dr. Narlikar also delved into her studies on heterochromatin protein 1 (HP1), highlighting how HP1 recognizes methylation marks and assembles on chromatin to facilitate gene silencing. This segment of the discussion underscored her shift to studying phase separation and its implications in the organization of chromatin. Notably, her lab made significant advancements in understanding how HP1 forms phase-separated droplets, a finding that was independently corroborated by other laboratories, demonstrating the utility of collaborative scientific inquiry.
In discussing the nuances of chromatin dynamics, Dr. Narlikar also introduced her investigations into the INO80 complex, detailing its distinct mechanism for nucleosome movement compared to other remodelers. Each remodeling complex, as she elucidated, has unique catalytic capabilities while still utilizing similar biochemical foundations, highlighting the diverse regulatory roles these proteins play within cells.
References* Racki LR, Yang JG, Naber N, Partensky PD, Acevedo A, Purcell TJ, Cooke R, Cheng Y, Narlikar GJ. The chromatin remodeller ACF acts as a dimeric motor to space nucleosomes. Nature. 2009 Dec 24;462(7276):1016-21. doi: 10.1038/nature08621. PMID: 20033039; PMCID: PMC2869534. * Canzio D, Liao M, Naber N, Pate E, Larson A, Wu S, Marina DB, Garcia JF, Madhani HD, Cooke R, Schuck P, Cheng Y, Narlikar GJ. A conformational switch in HP1 releases auto-inhibition to drive heterochromatin assembly. Nature. 2013 Apr 18;496(7445):377-81. doi: 10.1038/nature12032. Epub 2013 Mar 13. PMID: 23485968; PMCID: PMC3907283. * Sinha KK, Gross JD, Narlikar GJ. Distortion of histone octamer core promotes nucleosome mobilization by a chromatin remodeler. Science. 2017 Jan 20;355(6322):eaaa3761. doi: 10.1126/science.aaa3761. PMID: 28104838; PMCID: PMC5656449. * Larson AG, Elnatan D, Keenen MM, Trnka MJ, Johnston JB, Burlingame AL, Agard DA, Redding S, Narlikar GJ. Liquid droplet formation by HP1α suggests a role for phase separation in heterochromatin. Nature. 2017 Jul 13;547(7662):236-240. doi: 10.1038/nature22822. Epub 2017 Jun 21. PMID: 28636604; PMCID: PMC5606208. * Sanulli S, Trnka MJ, Dharmarajan V, Tibble RW, Pascal BD, Burlingame AL, Griffin PR, Gross JD, Narlikar GJ. HP1 reshapes nucleosome core to promote phase separation of heterochromatin. Nature. 2019 Nov;575(7782):390-394. doi: 10.1038/s41586-019-1669-2. Epub 2019 Oct 16. PMID: 31618757; PMCID: PMC7039410.
Related Episodes* Enhancers and Chromatin Remodeling in Mammary Gland Development (Camila dos Santos) * Heterochromatin Protein 1 and its Influence on the Structure of Chromatin (Serena Sanulli) * Heterochromatin and Phase Separation (Gary Karpen)
Contact* Epigenetics Podcast on Mastodon * Epigenetics Podcast on Bluesky * Dr. Stefan Dillinger on LinkedIn * Active Motif on LinkedIn * Active Motif on Bluesky * Email: podcast@activemotif.com
In this episode of the Epigenetics Podcast, we talked with Giacomo Cavalli from the Institute of Human Genetics in Montpellier about his work on critical aspects of epigenetic regulation, particularly the role of Polycomb proteins and chromatin architecture.
We start the Interview by talking about Dr. Cavalli's work on Polycomb function in maintaining chromatin states and how it relates to gene regulation. He shares insights from his early lab experiences, where he aimed to understand the inheritance mechanisms of chromatin states through various models, including the FAB7 cellular memory module. The discussion uncovers how Polycomb proteins can silence gene expression and the complex interplay between different epigenetic factors that govern this process.
Dr. Cavalli also addresses how he has investigated the recruitment mechanisms of Polycomb complexes, highlighting the roles of several DNA-binding proteins, including DSP-1 and GAGA factor, in this intricate regulatory landscape. He emphasizes the evolution of our understanding of Polycomb recruitment, illustrating the multifactorial nature of this biological puzzle.
As the conversation progresses, we explore Dr. Cavalli's fascinating research into the three-dimensional organization of the genome. He explains his contributions to mapping chromosomal interactions within Drosophila and the distinctions observed when performing similar studies in mammalian systems. Key findings regarding topologically associated domains (TADs) and their association with gene expression are presented, alongside the implications for our understanding of gene regulation in development and disease.
References Déjardin, J., Rappailles, A., Cuvier, O., Grimaud, C., Decoville, M., Locker, D., & Cavalli, G. (2005). Recruitment of Drosophila Polycomb group proteins to chromatin by DSP1. Nature, 434(7032), 533–538. https://doi.org/10.1038/nature03386 * Sexton, T., Yaffe, E., Kenigsberg, E., Bantignies, F., Leblanc, B., Hoichman, M., Parrinello, H., Tanay, A., & Cavalli, G. (2012). Three-dimensional folding and functional organization principles of the Drosophila genome. Cell, 148(3), 458–472. https://doi.org/10.1016/j.cell.2012.01.010 * Bonev, B., Mendelson Cohen, N., Szabo, Q., Fritsch, L., Papadopoulos, G. L., Lubling, Y., Xu, X., Lv, X., Hugnot, J. P., Tanay, A., & Cavalli, G. (2017). Multiscale 3D Genome Rewiring during Mouse Neural Development. Cell, 171(3), 557–572.e24. https://doi.org/10.1016/j.cell.2017.09.043 * Szabo, Q., Donjon, A., Jerković, I., Papadopoulos, G. L., Cheutin, T., Bonev, B., Nora, E. P., Bruneau, B. G., Bantignies, F., & Cavalli, G. (2020). Regulation of single-cell genome organization into TADs and chromatin nanodomains. Nature genetics, 52*(11), 1151–1157. https://doi.org/10.1038/s41588-020-00716-8
Related Episodes* BET Proteins and Their Role in Chromosome Folding and Compartmentalization (Kyle Eagen) * Long-Range Transcriptional Control by 3D Chromosome Structure (Luca Giorgetti) * Epigenetic Landscapes During Cancer (Luciano Di Croce)
Contact* Epigenetics Podcast on Mastodon * Epigenetics Podcast on Bluesky * Dr. Stefan Dillinger on LinkedIn * Active Motif on LinkedIn * Active Motif on Bluesky * Email: podcast@activemotif.com
In this episode of the Epigenetics Podcast, we talked with Ferdinand von Meyenn from ETH Zürich about his work on the interplay of nutrition, metabolic pathways, and epigenetic regulation.
To start Dr. Meyenn recounts his pivotal research on DNA methylation in naive embryonic stem cells during his time with Wolf Reick. He explains the dynamics of global demethylation in naive stem cells, revealing the key enzymes involved and the unexpected findings surrounding UHF1—its role in maintaining DNA methylation levels and influencing the methylation landscape during early embryonic development.
Dr. Meyenn then shares his perspective on the scientific transition to establishing his own lab at ETH. He reflects on his ambitions to merge the fields of metabolism and epigenetics, which is a recurring theme throughout his research. By investigating the interplay between metabolic changes and epigenetic regulation, he aims to uncover how environmental factors affect cellular dynamics across various tissues. This leads to a discussion of his recent findings on histone lactylation and its implications in cellular metabolism, as well as the intricacies of epigenetic imprinting in stem cell biology.
Last but not least we touch upon Dr. Meyenn’s most recent study, published in Nature, investigating the epigenetic effects of obesity. He provides a detailed overview of how adipose tissue undergoes transcriptional and epigenetic rearrangements during weight fluctuations. The conversation highlights the notion of epigenetic memory in adipocytes, showing how obesity is not just a temporary state but leaves lasting cellular changes that can predispose individuals to future weight regain after dieting. This exploration opens avenues for potential therapeutic interventions aimed at reversing adverse epigenetic modifications.
References von Meyenn, F., Iurlaro, M., Habibi, E., Liu, N. Q., Salehzadeh-Yazdi, A., Santos, F., Petrini, E., Milagre, I., Yu, M., Xie, Z., Kroeze, L. I., Nesterova, T. B., Jansen, J. H., Xie, H., He, C., Reik, W., & Stunnenberg, H. G. (2016). Impairment of DNA Methylation Maintenance Is the Main Cause of Global Demethylation in Naive Embryonic Stem Cells. Molecular cell, 62(6), 848–861. https://doi.org/10.1016/j.molcel.2016.04.025 * Galle, E., Wong, C. W., Ghosh, A., Desgeorges, T., Melrose, K., Hinte, L. C., Castellano-Castillo, D., Engl, M., de Sousa, J. A., Ruiz-Ojeda, F. J., De Bock, K., Ruiz, J. R., & von Meyenn, F. (2022). H3K18 lactylation marks tissue-specific active enhancers. Genome biology, 23(1), 207. https://doi.org/10.1186/s13059-022-02775-y * Agostinho de Sousa, J., Wong, C. W., Dunkel, I., Owens, T., Voigt, P., Hodgson, A., Baker, D., Schulz, E. G., Reik, W., Smith, A., Rostovskaya, M., & von Meyenn, F. (2023). Epigenetic dynamics during capacitation of naïve human pluripotent stem cells. Science advances, 9(39), eadg1936. https://doi.org/10.1126/sciadv.adg1936 * Bonder, M. J., Clark, S. J., Krueger, F., Luo, S., Agostinho de Sousa, J., Hashtroud, A. M., Stubbs, T. M., Stark, A. K., Rulands, S., Stegle, O., Reik, W., & von Meyenn, F. (2024). scEpiAge: an age predictor highlighting single-cell ageing heterogeneity in mouse blood. Nature communications, 15(1), 7567. https://doi.org/10.1038/s41467-024-51833-5 * Hinte, L. C., Castellano-Castillo, D., Ghosh, A., Melrose, K., Gasser, E., Noé, F., Massier, L., Dong, H., Sun, W., Hoffmann, A., Wolfrum, C., Rydén, M., Mejhert, N., Blüher, M., & von Meyenn, F. (2024). Adipose tissue retains an epigenetic memory of obesity after weight loss. Nature, 636*(8042), 457–465. https://doi.org/10.1038/s41586-024-08165-7
Related Episodes* Nutriepigenetics: The Effects of Diet on Behavior (Monica Dus) * Epigenetic and Metabolic Regulation of Early Development (Jan Żylicz) * Effects of Environmental Cues on the Epigenome and Longevity (Paul Shiels)
Contact* Epigenetics Podcast on Mastodon * Epigenetics Podcast on Bluesky * Dr. Stefan Dillinger on LinkedIn * Active Motif on LinkedIn * Active Motif on Bluesky * Email: podcast@activemotif.com
In this episode of the Epigenetics Podcast, we talked with Vijay Ramani from the Gladstone Institute about his work on Single-Molecule Adenine Methylated Oligonucleosome Sequencing Assay (SAMOSA).
Our discussion starts with Vijay Ramani's impactful contributions to the field during his time in Jay Shendure's lab, where he worked on several innovative methods, including RNA proximity ligation. This project was conceived during his graduate studies, aiming to adapt techniques from DNA research to investigate RNA structures—a largely unexplored area at the time. We delved into the nuances of his experiences in graduate school, emphasizing how critical it was to have mentors who provided room for creativity and autonomy in experimental design.
Dr. Ramani then shares insights about his foray into developing more refined methodologies, such as in-situ DNA Hi-C, a revolutionary protocol tailored for three-dimensional genomic mapping. He explained the rationale behind his projects, comparing the outcomes with contemporaneous advancements in methods like Micro-C. The discussion highlighted the importance of understanding enzyme bias in chromatin studies and the need for meticulous experimental design to ensure the validity of biological interpretations.
We further explored exciting advancements in single-cell genomics, specifically Ramani's work on developing sci-Hi-C. This innovative technique leverages combinatorial indexing to allow high-resolution mapping of chromatin architecture at the single-cell level, a significant leap forward in understanding the complexities of gene regulation.
As we progress, Ramani detailed his transition from graduate student to independent investigator starting his own lab. He elaborated on the challenges and excitements associated with establishing his research focus in chromatin structure and function using advanced sequencing technologies. Employing various strategies, including the innovative SAMOSA assay, his research seeks to elucidate the mechanisms by which chromatin structure influences transcriptional regulation.
We also discussed the heterogeneity of chromatin and its implications for gene expression. Ramani provided a fascinating perspective on how variations in chromatin structure could affect gene activity, highlighting potential avenues for future research that aims to untangle the complex dynamics at play in both healthy and diseased states.
References Ramani, V., Cusanovich, D., Hause, R. et al. Mapping 3D genome architecture through in situ DNase Hi-C. Nat Protoc 11, 2104–2121 (2016). https://doi.org/10.1038/nprot.2016.126 * Nour J Abdulhay, Colin P McNally, Laura J Hsieh, Sivakanthan Kasinathan, Aidan Keith, Laurel S Estes, Mehran Karimzadeh, Jason G Underwood, Hani Goodarzi, Geeta J Narlikar, Vijay Ramani (2020) Massively multiplex single-molecule oligonucleosome footprinting eLife 9:e59404. https://doi.org/10.7554/eLife.59404 * Abdulhay, N.J., Hsieh, L.J., McNally, C.P. et al. Nucleosome density shapes kilobase-scale regulation by a mammalian chromatin remodeler. Nat Struct Mol Biol 30, 1571–1581 (2023). https://doi.org/10.1038/s41594-023-01093-6 * Nanda, A.S., Wu, K., Irkliyenko, I. et al. Direct transposition of native DNA for sensitive multimodal single-molecule sequencing. Nat Genet* 56, 1300–1309 (2024). https://doi.org/10.1038/s41588-024-01748-0
Related Episodes* Epigenetic Mechanisms in Genome Regulation and Developmental Programming (James Hackett) * Chromatin Profiling: From ChIP to CUT&RUN, CUT&Tag and CUTAC (Steven Henikoff) * Split-Pool Recognition of Interactions by Tag Extension (SPRITE) (Mitch Guttman)
Contact* Epigenetics Podcast on X * Epigenetics Podcast on Instagram * Epigenetics Podcast on Mastodon * Epigenetics Podcast on Bluesky * Epigenetics Podcast on Threads * Active Motif on X * Active Motif on LinkedIn * Email: podcast@activemotif.com
In this episode of the Epigenetics Podcast, we talked with Maxim Greenberg from the Institute Jacob Monot about his work on epigenetic consequences of DNA methylation in development.
In this interview we explore how Dr. Greenberg’s work at UCLA involved pioneering experiments on DNA methylation mechanisms and how this period was marked by significant collaborative efforts within a highly competitive yet supportive lab environment that ultimately lead to publications in high impact journals.
His transition to a postdoctoral position at the Institut Curie with Deborah Bourc'his harnessed his expertise in mammalian systems, examining chromatin changes and the implications for embryonic development. Dr. Greenberg explained the nuances of his research, particularly how chromatin modifications during early development can influence gene regulatory mechanisms later in life, providing a compelling narrative about the potential long-term impacts of epigenetic changes that occur in utero.
Throughout our conversation, we examined the intricate relationship between DNA methylation and Polycomb repression, discussing how these epigenetic mechanisms interact and the functional outcomes of their regulation. Dr. Greenberg's insights into his recent studies reveal a commitment to unraveling the complexities of enhancer-promoter interactions in the context of epigenetic regulation.
References Greenberg, M. V., Ausin, I., Chan, S. W., Cokus, S. J., Cuperus, J. T., Feng, S., Law, J. A., Chu, C., Pellegrini, M., Carrington, J. C., & Jacobsen, S. E. (2011). Identification of genes required for de novo DNA methylation in Arabidopsis. Epigenetics, 6(3), 344–354. https://doi.org/10.4161/epi.6.3.14242 * Greenberg, M. V., Glaser, J., Borsos, M., Marjou, F. E., Walter, M., Teissandier, A., & Bourc'his, D. (2017). Transient transcription in the early embryo sets an epigenetic state that programs postnatal growth. Nature genetics, 49(1), 110–118. https://doi.org/10.1038/ng.3718 * Greenberg, M., Teissandier, A., Walter, M., Noordermeer, D., & Bourc'his, D. (2019). Dynamic enhancer partitioning instructs activation of a growth-related gene during exit from naïve pluripotency. eLife, 8, e44057. https://doi.org/10.7554/eLife.44057 * Monteagudo-Sánchez, A., Richard Albert, J., Scarpa, M., Noordermeer, D., & Greenberg, M. V. C. (2024). The impact of the embryonic DNA methylation program on CTCF-mediated genome regulation. Nucleic acids research, 52(18), 10934–10950. https://doi.org/10.1093/nar/gkae724 * Richard Albert, J., Urli, T., Monteagudo-Sánchez, A., Le Breton, A., Sultanova, A., David, A., Scarpa, M., Schulz, M., & Greenberg, M. V. C. (2024). DNA methylation shapes the Polycomb landscape during the exit from naive pluripotency. Nature structural & molecular biology*, 10.1038/s41594-024-01405-4. Advance online publication. https://doi.org/10.1038/s41594-024-01405-4
Related Episodes* DNA Methylation and Mammalian Development (Déborah Bourc'his) * Circulating Epigenetic Biomarkers in Cancer (Charlotte Proudhon) * Epigenetic Mechanisms in Genome Regulation and Developmental Programming (James Hackett)
Contact* Epigenetics Podcast on Mastodon * Epigenetics Podcast on Bluesky * Dr. Stefan Dillinger on LinkedIn * Active Motif on LinkedIn * Active Motif on Bluesky * Email: podcast@activemotif.com
In this episode of the Epigenetics Podcast, we talked with Natalia Gromak from the University of Oxford about her work on R-Loop biology in health and disease.
In this interview Dr. Gromak delves into her significant research on transcription and RNA biology, particularly focusing on the molecular mechanisms involved at transcriptional pause sites. She describes her early work in understanding transcription termination and how her team investigated the role of specific RNA and DNA structures, including R-loops, that could influence polymerase progression. This exploration into R-loops—complexes formed by RNA and DNA interactions—was a key turning point in her research, as she and her colleagues identified their regulatory functions within the human genome.
Discussion transitions into her findings regarding the implications of R-loops in diseases like Friedrich's ataxia and Fragile X syndrome. Dr. Gromak then elucidates how the pathological expansion of repeat sequences in these conditions interferes with normal gene expression, and how R-loops exacerbate transcriptional silencing. Throughout her reflection on these discoveries, she emphasizes the importance of studying R-loops beyond merely being a transcriptional byproduct, but as players in gene regulation and potential contributors to disease pathology.
The episode also covers her innovative work in characterizing the R-loop interactome through various experimental techniques. She highlights the complexity of R-loop dynamics, including the discovery of protein factors that interact with R-loops and could influence their stability and regulatory functions. Furthermore, she discusses the exciting intersection of RNA modifications, such as m6A, which plays a role in R-loop regulation and presents new avenues for research, particularly pertaining to how disease-specific modifications might alter R-loop behavior.
References Cristini, A., Groh, M., Kristiansen, M. S., & Gromak, N. (2018). RNA/DNA Hybrid Interactome Identifies DXH9 as a Molecular Player in Transcriptional Termination and R-Loop-Associated DNA Damage. Cell reports, 23(6), 1891–1905. https://doi.org/10.1016/j.celrep.2018.04.025 * Abakir, A., Giles, T. C., Cristini, A., Foster, J. M., Dai, N., Starczak, M., Rubio-Roldan, A., Li, M., Eleftheriou, M., Crutchley, J., Flatt, L., Young, L., Gaffney, D. J., Denning, C., Dalhus, B., Emes, R. D., Gackowski, D., Corrêa, I. R., Jr, Garcia-Perez, J. L., Klungland, A., … Ruzov, A. (2020). N6-methyladenosine regulates the stability of RNA:DNA hybrids in human cells. Nature genetics, 52*(1), 48–55. https://doi.org/10.1038/s41588-019-0549-x
Related Episodes* DNA Replication, Transcription and R-loops (Stephan Hamperl)
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In this episode of the Epigenetics Podcast, we talked with Yadira Soto-Feliciano from MIT about her work on the Menin-MLL complex and the effect of small molecules on its stability in leukemia.
We explore the pivotal moments that led her to cancer biology during her graduate studies, where her work included ground-breaking research on the role of the plant homeodomain Finger protein-6 (PHF-6) in leukemia. This work bridged the realms of chromatin accessibility, transcription factors, and cancer cell lineage, providing critical evidence for the concept of lineage plasticity in cancer biology—a topic that has gained significant traction in recent years. Dr. Soto-Feliciano discusses how advances in techniques like CRISPR and ChIP-sequencing have shaped her research, enabling deeper insights into the mechanisms underlying cancer cell identity.
As our discussion transitions, Dr. Soto-Feliciano shares her experience in David Allis's lab, illustrating how the collaboration across diverse scientific disciplines enhanced her understanding of chromatin biology and generated significant insights into the mechanics of epigenetic regulation. Highlighting a recent 2023 publication, we unpack her findings related to the conserved molecular switch between MLL1 and MLL3 complexes. These discoveries revealed how the application of small-molecule inhibitors of the menin-MLL interaction can alter gene expression and affect leukemia cells’ responses to treatments.
We also touch on the operational dynamics within her lab at MIT, established during challenging times marked by the pandemic. Yadira is dedicated to fostering a collaborative and respectful environment among her team, comprised of PhD candidates and research technicians, all sharing a commitment to unraveling the complexities of chromatin regulation. She emphasizes the significance of understanding chromatin scaffold proteins and their role in regulating gene expression and genome organization.
References Soto-Feliciano, Y. M., Bartlebaugh, J. M. E., Liu, Y., Sánchez-Rivera, F. J., Bhutkar, A., Weintraub, A. S., Buenrostro, J. D., Cheng, C. S., Regev, A., Jacks, T. E., Young, R. A., & Hemann, M. T. (2017). PHF6 regulates phenotypic plasticity through chromatin organization within lineage-specific genes. Genes & development, 31(10), 973–989. https://doi.org/10.1101/gad.295857.117 * Soto-Feliciano, Y. M., Sánchez-Rivera, F. J., Perner, F., Barrows, D. W., Kastenhuber, E. R., Ho, Y. J., Carroll, T., Xiong, Y., Anand, D., Soshnev, A. A., Gates, L., Beytagh, M. C., Cheon, D., Gu, S., Liu, X. S., Krivtsov, A. V., Meneses, M., de Stanchina, E., Stone, R. M., Armstrong, S. A., … Allis, C. D. (2023). A Molecular Switch between Mammalian MLL Complexes Dictates Response to Menin-MLL Inhibition. Cancer discovery, 13(1), 146–169. https://doi.org/10.1158/2159-8290.CD-22-0416 * Zhu, C., Soto-Feliciano, Y. M., Morris, J. P., Huang, C. H., Koche, R. P., Ho, Y. J., Banito, A., Chen, C. W., Shroff, A., Tian, S., Livshits, G., Chen, C. C., Fennell, M., Armstrong, S. A., Allis, C. D., Tschaharganeh, D. F., & Lowe, S. W. (2023). MLL3 regulates the CDKN2A tumor suppressor locus in liver cancer. eLife, 12*, e80854. https://doi.org/10.7554/eLife.80854
Related Episodes* MLL Proteins in Mixed-Lineage Leukemia (Yali Dou) * Targeting COMPASS to Cure Childhood Leukemia (Ali Shilatifard)
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In this episode of the Epigenetics Podcast, we talked with Mary Anne Jelinek Associate Director of R&D at Active Motif about writing and reviewing grants in academia and industry. Learn from Dr. Jelinek’s years of experience writing and reviewing grants and get her best advice and insight for success. Hear about similarities and differences in preparing grants in academia vs. biotech or other industry settings. Key insights include:
- Finding Grant opportunities that exist for different sectors and countries, from the familiar ones like NIH and NSF in the United States grant funding offered by NATO for member countries.
- Learn about grants targeted to small businesses and specific allocation of resources intended to foster and promote innovation and entrepreneurship and how to navigate confidentiality when writing grants in industry, being mindful of conflict of interest and best practices.
- Coming up with ideas is easy – but how do you find institutes interested in funding those research areas? Get tips on how to submit a 1-page inquiry for feedback and guidance at early stages that will help your grant be robust and successful.
Think you can go from idea to funding in 4 weeks? She has and discusses the best strategy to do this - collaboration is key and you’ll learn why. Get tips on wording and writing for reviewers who may not be experts in your field and how to “paint a picture” that makes it both clear and persuasive, including your writing style and use of diagrams and figures for those complex concepts. Hear all of Dr. Jelinek’s “best advice” and encouragement for dealing with stress and frustration that can be part of the process.
Finally, as a co-developer for the first commercially available ChIP Kit, Dr. Jelinek tells the story of how this assay developed and became a gold-standard method for epigenetics.
Tune in to this in depth and very helpful episode!
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In this episode of the Epigenetics Podcast, we talked with Carl Wu from John's Hopkins University about his work on nucleosome remodeling, histone variants, and the role of single-molecule imaging in gene regulation.
Our discussion starts with Carl Wu sharing his first significant milestones, a paper in "Cell" and the serendipitous discovery of DNA hypersensitive sites, which transformed our understanding of chromatin accessibility and its implications for gene regulation.
As we delve into Dr. Wu’s specific areas of research, he elaborates on the biochemistry of nucleosome remodeling and the intricate role of chromatin remodeling enzymes like NURF. We discuss how these enzymes employ ATP hydrolysis to reposition nucleosomes, making DNA accessible for transcription. He then explains the collaborative relationship between chromatin remodelers and transcription factors, showcasing the fascinating interplay that governs gene expression and regulatory mechanisms.
The conversation takes a deeper turn as we explore Carl Wu’s groundbreaking studies on histone variants, particularly H2AZ. He elucidates the role of SWR1 in facilitating the exchange between H2A and H2AZ in nucleosome arrays. The high-resolution structural insights garnered from recent studies reveal how the enzyme mediates histone eviction and insertion with remarkable precision, providing a clearer picture of chromatin dynamics at a molecular level.
References Wu, C., Bingham, P. M., Livak, K. J., Holmgren, R., & Elgin, S. C. (1979). The chromatin structure of specific genes: I. Evidence for higher order domains of defined DNA sequence. Cell, 16(4), 797–806. https://doi.org/10.1016/0092-8674(79)90095-3 * Wu, C., Wong, Y. C., & Elgin, S. C. (1979). The chromatin structure of specific genes: II. Disruption of chromatin structure during gene activity. Cell, 16(4), 807–814. https://doi.org/10.1016/0092-8674(79)90096-5 * Wu C. (1980). The 5' ends of Drosophila heat shock genes in chromatin are hypersensitive to DNase I. Nature, 286(5776), 854–860. https://doi.org/10.1038/286854a0 * Wu, C., Wilson, S., Walker, B., Dawid, I., Paisley, T., Zimarino, V., & Ueda, H. (1987). Purification and properties of Drosophila heat shock activator protein. Science (New York, N.Y.), 238(4831), 1247–1253. https://doi.org/10.1126/science.3685975 * Mizuguchi, G., Shen, X., Landry, J., Wu, W. H., Sen, S., & Wu, C. (2004). ATP-driven exchange of histone H2AZ variant catalyzed by SWR1 chromatin remodeling complex. Science (New York, N.Y.), 303(5656), 343–348. https://doi.org/10.1126/science.1090701 * Kim, J. M., Visanpattanasin, P., Jou, V., Liu, S., Tang, X., Zheng, Q., Li, K. Y., Snedeker, J., Lavis, L. D., Lionnet, T., & Wu, C. (2021). Single-molecule imaging of chromatin remodelers reveals role of ATPase in promoting fast kinetics of target search and dissociation from chromatin. eLife, 10*, e69387. https://doi.org/10.7554/eLife.69387
Related Episodes* Multiple challenges of ATAC-Seq, Points to Consider (Yuan Xue) * Pioneer Transcription Factors and Their Influence on Chromatin Structure (Ken Zaret) * ATAC-Seq, scATAC-Seq and Chromatin Dynamics in Single-Cells (Jason Buenrostro)
Contact* Epigenetics Podcast on X * Epigenetics Podcast on Instagram * Epigenetics Podcast on Mastodon * Epigenetics Podcast on Bluesky * Epigenetics Podcast on Threads * Active Motif on X * Active Motif on LinkedIn * Email: podcast@activemotif.com
In this episode of the Epigenetics Podcast, we talked with Mitinori Saitou from Kyoto University about his work on germ cell development, focusing on proteins like BLIMP1 and PRDM14, reprogramming iPSCs, and his vision to address infertility and genetic disorders through epigenetic insights.
To start our discussion, Dr. Saitou shares the foundation of his research, which centers on the mechanisms of germ cell development across various species, including mice, non-human primates, and humans. He provides insight into his early work examining the roles of two key proteins: BLIMP1 and PRDM14. These proteins are essential for germline specification in mammals, and their functions are unveiled through detailed exploration of knockout models. In particular, Dr. Saitou elucidates the critical events in germ cell specification, highlighting how disruptions to the functions of these proteins lead to significant impairments in development.
As the conversation deepens, we discuss Dr. Saitou’s groundbreaking advances in human-induced pluripotent stem cells (iPSCs). He elaborates on the processes involved in reprogramming these cells to form primordial germ cell-like cells, emphasizing the significance of understanding various cellular contexts and transcriptional regulation. Dr. Saitou then details how overexpression of certain factors in embryonic stem cells can induce these germline characteristics, presenting the promise of innovation in regenerative medicine and reproductive biology.
We end our talk with the exploration of chromatin remodeling that occurs during germ cell development, including fascinating details about DNA and histone modification dynamics. Dr. Saitou articulates how the epigenetic landscape shifts during the transition from pluripotent states to germ cell specification, providing a detailed comparison between mouse and human systems. This highlights the complexity of gene regulation and the importance of specific epigenetic markers in establishing and maintaining cellular identity.
References Yamaji, M., Seki, Y., Kurimoto, K. et al. Critical function of Prdm14 for the establishment of the germ cell lineage in mice. Nat Genet 40, 1016–1022 (2008). https://doi.org/10.1038/ng.186 * Katsuhiko Hayashi et al., Offspring from Oocytes Derived from in Vitro Primordial Germ Cell–like Cells in Mice. Science 338, 971-975 (2012). DOI: 10.1126/science.1226889 * Nakaki, F., Hayashi, K., Ohta, H. et al. Induction of mouse germ-cell fate by transcription factors in vitro. Nature 501, 222–226 (2013). https://doi.org/10.1038/nature12417 * Nakamura, T., Okamoto, I., Sasaki, K. et al. A developmental coordinate of pluripotency among mice, monkeys and humans. Nature 537, 57–62 (2016). https://doi.org/10.1038/nature19096 * Murase, Y., Yokogawa, R., Yabuta, Y. et al. In vitro reconstitution of epigenetic reprogramming in the human germ line. Nature* 631, 170–178 (2024). https://doi.org/10.1038/s41586-024-07526-6
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In this episode of the Epigenetics Podcast, we talked with Karine Le Roch from the University of California at Riverside about her work on malaria chromatin structure and its transcriptional regulation.
In this Interview Dr. Le Roch discusses her investigation of post-transcriptional controls and nucleosome positioning in Plasmodium falciparum, employing next-generation sequencing and chromatin profiling methods. Karin emphasizes how these methodologies contribute to a comprehensive understanding of gene regulation beyond mere transcription initiation, emphasizing the significance of mRNA binding proteins and their role in stabilizing gene transcripts for translation. This exploration of the interaction between chromatin structure, transcriptional dynamics, and post-transcriptional regulation reveals a multidimensional perspective of gene expression.
Transitioning to her lab’s focus on high-throughput genomic technologies, we discuss how Karin and her team are uncovering conserved and species-specific genomic organization principles within various Plasmodium species. By generating 3D genomic models through Hi-C experiments, she describes how they have identified patterns that underline the parasite's immune evasion strategies. In particular, we learn how genes involved in antigenic variation are controlled through intricate epigenetic mechanisms, illuminating the pathways that allow these parasites to elude host immune responses.
References Le Roch, K. G., Zhou, Y., Blair, P. L., Grainger, M., Moch, J. K., Haynes, J. D., De La Vega, P., Holder, A. A., Batalov, S., Carucci, D. J., & Winzeler, E. A. (2003). Discovery of gene function by expression profiling of the malaria parasite life cycle. Science (New York, N.Y.), 301(5639), 1503–1508. https://doi.org/10.1126/science.1087025 * Ponts, N., Harris, E. Y., Prudhomme, J., Wick, I., Eckhardt-Ludka, C., Hicks, G. R., Hardiman, G., Lonardi, S., & Le Roch, K. G. (2010). Nucleosome landscape and control of transcription in the human malaria parasite. Genome research, 20(2), 228–238. https://doi.org/10.1101/gr.101063.109 * Bunnik, E. M., Cook, K. B., Varoquaux, N., Batugedara, G., Prudhomme, J., Cort, A., Shi, L., Andolina, C., Ross, L. S., Brady, D., Fidock, D. A., Nosten, F., Tewari, R., Sinnis, P., Ay, F., Vert, J. P., Noble, W. S., & Le Roch, K. G. (2018). Changes in genome organization of parasite-specific gene families during the Plasmodium transmission stages. Nature communications, 9*(1), 1910. https://doi.org/10.1038/s41467-018-04295-5
Related Episodes* Epigenetics in Human Malaria Parasites (Elena Gómez-Diaz)
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In this episode of the Epigenetics Podcast, we talked with Bas van Steensel from the Netherlands Cancer Institute about his work on characterizing chromatin at the Nuclear Lamina.
The Interview starts with discussing Bas van Steensel's significant contributions to understanding genome-nuclear lamina interactions. Bas detailed the development of the DAM-ID technique during his postdoctoral studies, which provided a novel way to map genome-wide occupancy and identify Lamina-Associated Domains (LADs). He elaborated on how LADs reveal a distinct domain architecture, often correlating with gene expression levels. This prompted an exploration of the dynamics of these domains during differentiation processes, allowing insights into how gene activation and repression are influenced by their positioning relative to the nuclear lamina.
The conversation highlighted the intricate relationship between chromatin dynamics and gene regulation, with Bas sharing compelling findings on how LADs behave during cell differentiation. The research indicated that regions moving away from the lamina often correlated with increased gene expression, revealing a complex interplay of spatial genome organization and transcriptional activity.
Additionally, we ventured into the significance of outreach and transparency in scientific research. Bas shared his philosophy regarding collaboration and the ethical responsibility of scientists to share knowledge and resources openly. He emphasized that making lab notebooks and research processes accessible can greatly enhance reproducibility and understanding in the scientific community.
References Open Science Policy of our lab * Guelen, L., Pagie, L., Brasset, E., Meuleman, W., Faza, M. B., Talhout, W., Eussen, B. H., de Klein, A., Wessels, L., de Laat, W., & van Steensel, B. (2008). Domain organization of human chromosomes revealed by mapping of nuclear lamina interactions. Nature, 453(7197), 948–951. https://doi.org/10.1038/nature06947 * Kind, J., Pagie, L., Ortabozkoyun, H., Boyle, S., de Vries, S. S., Janssen, H., Amendola, M., Nolen, L. D., Bickmore, W. A., & van Steensel, B. (2013). Single-cell dynamics of genome-nuclear lamina interactions. Cell, 153(1), 178–192. https://doi.org/10.1016/j.cell.2013.02.028 * Kind, J., Pagie, L., de Vries, S. S., Nahidiazar, L., Dey, S. S., Bienko, M., Zhan, Y., Lajoie, B., de Graaf, C. A., Amendola, M., Fudenberg, G., Imakaev, M., Mirny, L. A., Jalink, K., Dekker, J., van Oudenaarden, A., & van Steensel, B. (2015). Genome-wide maps of nuclear lamina interactions in single human cells. Cell, 163(1), 134–147. https://doi.org/10.1016/j.cell.2015.08.040 * Leemans, C., van der Zwalm, M. C. H., Brueckner, L., Comoglio, F., van Schaik, T., Pagie, L., van Arensbergen, J., & van Steensel, B. (2019). Promoter-Intrinsic and Local Chromatin Features Determine Gene Repression in LADs. Cell, 177(4), 852–864.e14. https://doi.org/10.1016/j.cell.2019.03.009 * van Schaik, T., Liu, N. Q., Manzo, S. G., Peric-Hupkes, D., de Wit, E., & van Steensel, B. (2022). CTCF and cohesin promote focal detachment of DNA from the nuclear lamina. Genome biology, 23(1), 185. https://doi.org/10.1186/s13059-022-02754-3 * van Steensel B. (2018). Scientific honesty and publicly shared lab notebooks: Sharing lab notebooks along with publication would increase transparency and help to improve honesty when reporting results. EMBO reports, 19*(10), e46866. https://doi.org/10.15252/embr.201846866
Related Episodes* scDamID, EpiDamID and Lamina Associated Domains (Jop Kind) * Identification of Functional Elements in the Genome (Bing Ren) * Chromatin Profiling: From ChIP to CUT&RUN, CUT&Tag and CUTAC (Steven Henikoff)
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In this episode of the Epigenetics Podcast, we caught up with Vladimir Teif from the University of Essex to talk about his work on nucleosome positioning in development and disease.
Vladimir's research has been pivotal in understanding nucleosome positioning and its implications for cell differentiation, particularly in embryonic stem cells and cancer. We discuss his groundbreaking studies that first mapped nucleosome positions in various cell types and how these findings led to uncovering the intricate relationships between nucleosome stability, transcription factors, and DNA modifications such as methylation. This understanding has immense significance for cancer diagnostics, where knowing the spatial arrangement of nucleosomes could influence how aggressive a cancer type might be, or how a patient might respond to treatment.
Transitioning from foundational research to clinical applications, Vladimir elaborates on his exciting work with liquid biopsies. By analyzing cell-free DNA from blood plasma, researchers can infer the nucleosome positioning and, ultimately, the presence of cancer without the need for invasive tissue biopsies. We explore how this new approach holds potential for earlier detection of cancers and more effective patient stratification, demonstrating a profound shift in how we leverage epigenetic data in clinical settings.
References
- Vladimir B. Teif, Karsten Rippe, Predicting nucleosome positions on the DNA: combining intrinsic sequence preferences and remodeler activities, Nucleic Acids Research, Volume 37, Issue 17, 1 September 2009, Pages 5641–5655, https://doi.org/10.1093/nar/gkp610
- Teif, V., Vainshtein, Y., Caudron-Herger, M. et al. Genome-wide nucleosome positioning during embryonic stem cell development. Nat Struct Mol Biol 19, 1185–1192 (2012). https://doi.org/10.1038/nsmb.2419
- Beshnova DA, Cherstvy AG, Vainshtein Y, Teif VB (2014) Regulation of the Nucleosome Repeat Length In Vivo by the DNA Sequence, Protein Concentrations and Long-Range Interactions. PLoS Comput Biol 10(7): e1003698. https://doi.org/10.1371/journal.pcbi.1003698
- Shtumpf, M., Piroeva, K.V., Agrawal, S.P. et al. NucPosDB: a database of nucleosome positioning in vivo and nucleosomics of cell-free DNA. Chromosoma 131, 19–28 (2022). https://doi.org/10.1007/s00412-021-00766-9
Related Episodes
- Circulating Epigenetic Biomarkers in Cancer (Charlotte Proudhon)
- Epigenome-based Precision Medicine (Eleni Tomazou)
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In this episode of the Epigenetics Podcast, we talked with Johnathan Whetstine from Fox Chase Cancer Center about his work on how histone demethylases affect gene expression and cancer cell stability.
The Interview start by discussing a pivotal paper from Jonathan's lab in 2010, where they identified a role for the KDM4A histone demethylase in replication timing and cell cycle progression. They elaborate on the discoveries made regarding the link between histone marks, replication timing, and gene expression control. Jonathan explains the impact of microRNAs on regulating KDM4A and how protein turnover rates can influence cellular responses to treatments like mTOR inhibitors.
Further, they explore the causal relationship between histone marks and replication timing, demonstrating how alterations in epigenetic regulation can affect genome stability. Jonathan shares insights from his latest research on H3K9 methylation balance at the MLL-KM2A locus, elucidating how these epigenetic modifications regulate amplifications and rearrangements in cancer cells. The episode concludes with a discussion on the establishment of the Cancer Epigenetics Institute at Fox Chase Cancer Center, aiming to bridge academia and industry to accelerate translational research in cancer epigenetics.
References Black, J. C., Allen, A., Van Rechem, C., Forbes, E., Longworth, M., Tschöp, K., Rinehart, C., Quiton, J., Walsh, R., Smallwood, A., Dyson, N. J., & Whetstine, J. R. (2010). Conserved antagonism between JMJD2A/KDM4A and HP1γ during cell cycle progression. Molecular cell, 40(5), 736–748. https://doi.org/10.1016/j.molcel.2010.11.008 * Mishra, S., Van Rechem, C., Pal, S., Clarke, T. L., Chakraborty, D., Mahan, S. D., Black, J. C., Murphy, S. E., Lawrence, M. S., Daniels, D. L., & Whetstine, J. R. (2018). Cross-talk between Lysine-Modifying Enzymes Controls Site-Specific DNA Amplifications. Cell, 174(4), 803–817.e16. https://doi.org/10.1016/j.cell.2018.06.018 * Van Rechem, C., Ji, F., Chakraborty, D., Black, J. C., Sadreyev, R. I., & Whetstine, J. R. (2021). Collective regulation of chromatin modifications predicts replication timing during cell cycle. Cell reports, 37(1), 109799. https://doi.org/10.1016/j.celrep.2021.109799 * Gray, Z. H., Chakraborty, D., Duttweiler, R. R., Alekbaeva, G. D., Murphy, S. E., Chetal, K., Ji, F., Ferman, B. I., Honer, M. A., Wang, Z., Myers, C., Sun, R., Kaniskan, H. Ü., Toma, M. M., Bondarenko, E. A., Santoro, J. N., Miranda, C., Dillingham, M. E., Tang, R., Gozani, O., … Whetstine, J. R. (2023). Epigenetic balance ensures mechanistic control of MLL amplification and rearrangement. Cell, 186*(21), 4528–4545.e18. https://doi.org/10.1016/j.cell.2023.09.009
Related Episodes* The Impact of Chromatin Modifiers on Disease Development and Progression (Capucine van Rechem)
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In this episode of the Epigenetics Podcast, we talked with Christa Bruecker from the Max Perutz Laboratories in Vienna about her work on transcriptional regulation during early embryonic development.
Christa Buecker unravels the differences between naive and primed pluripotency states, showcasing how OCT4 relocalization and enhancer chromatin landscapes play pivotal roles during this transition. The conversation delves into the intricate interplay of transcription factors like OCT4 and OTX2, shedding light on their collaborative efforts in regulating gene expression during differentiation.
Dr. Bücker then shares insights from her study on enhancer elements controlling FGF5 expression and discusses the surprising revelation that individual enhancers show no intrinsic activity but work together in a super additive fashion. She also touches upon her research on IRF1's connection to the gene regulatory network and its role in protecting cells against viral infections.
The conversation shifts to Dr. Bücker's current research endeavors, focusing on exploring the strength of enhancers and their impact on gene expression at different distances from promoters. She shares her vision for future experiments and the integration of enhancers to decipher their impact on transcription regulation.
References Buecker, C., Srinivasan, R., Wu, Z., Calo, E., Acampora, D., Faial, T., Simeone, A., Tan, M., Swigut, T., & Wysocka, J. (2014). Reorganization of enhancer patterns in transition from naive to primed pluripotency. Cell stem cell, 14(6), 838–853. https://doi.org/10.1016/j.stem.2014.04.003 * Thomas, H. F., Kotova, E., Jayaram, S., Pilz, A., Romeike, M., Lackner, A., Penz, T., Bock, C., Leeb, M., Halbritter, F., Wysocka, J., & Buecker, C. (2021). Temporal dissection of an enhancer cluster reveals distinct temporal and functional contributions of individual elements. Molecular cell, 81(5), 969–982.e13. https://doi.org/10.1016/j.molcel.2020.12.047 * Romeike, M., Spach, S., Huber, M., Feng, S., Vainorius, G., Elling, U., Versteeg, G. A., & Buecker, C. (2022). Transient upregulation of IRF1 during exit from naive pluripotency confers viral protection. EMBO reports, 23*(9), e55375. https://doi.org/10.15252/embr.202255375
Related Episodes* Enhancer Communities in Adipocyte Differentiation (Susanne Mandrup) * Enhancer-Promoter Interactions During Development (Yad Ghavi-Helm) * Enhancers and Chromatin Remodeling in Mammary Gland Development (Camila dos Santos) * Ultraconserved Enhancers and Enhancer Redundancy (Diane Dickel)
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In this episode of the Epigenetics Podcast, we talked with Claire Rougeulle from the Epigenetics and Cell Fate Center at Université Paris City on this show to talk about her work on gene expression control, the intricacies of X-chromosome inactivation, and the potential of non-coding RNAs in this process.
In this episode Claire Rougeulle explains her discoveries regarding the transcription regulation of XIST by factors like YY1 and the erosion of X-chromosome inactivation in human pluripotent stem cells. She shares the complexity of distinguishing between epigenetics and transcriptional regulation, highlighting the challenges in studying allelic expression of X-chromosomes at the single-cell level.
The Episode further explores Claire's findings on the XACT locus regulation, evolution from retroviruses, and its potential role in preventing X-chromosome silencing. Claire also shares her future research focus on understanding X-inactivation establishment in humans and the transition from XIST attenuating to silencing X-chromosomes after implantation.
References Makhlouf, M., Ouimette, J. F., Oldfield, A., Navarro, P., Neuillet, D., & Rougeulle, C. (2014). A prominent and conserved role for YY1 in Xist transcriptional activation. Nature communications, 5, 4878. https://doi.org/10.1038/ncomms5878 * Vallot, C., Ouimette, J. F., Makhlouf, M., Féraud, O., Pontis, J., Côme, J., Martinat, C., Bennaceur-Griscelli, A., Lalande, M., & Rougeulle, C. (2015). Erosion of X Chromosome Inactivation in Human Pluripotent Cells Initiates with XACT Coating and Depends on a Specific Heterochromatin Landscape. Cell stem cell, 16(5), 533–546. https://doi.org/10.1016/j.stem.2015.03.016 * Casanova, M., Moscatelli, M., Chauvière, L. É., Huret, C., Samson, J., Liyakat Ali, T. M., Rosspopoff, O., & Rougeulle, C. (2019). A primate-specific retroviral enhancer wires the XACT lncRNA into the core pluripotency network in humans. Nature communications, 10*(1), 5652. https://doi.org/10.1038/s41467-019-13551-1
Related Episodes* Epigenetics and X-Inactivation (Edith Heard) * Investigating the Dynamics of Epigenetic Plasticity in Cancer with Single Cell Technologies (Céline Vallot)
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In this episode of the Epigenetics Podcast, we talked with James Hackett from the EMBL in Rome about his work on epigenetic mechanisms in genome regulation and developmental programming.
One of James Hackett's significant studies focused on DNA methylation and genome defense mechanisms in the germline, exploring the role of chromatin modifications in mammalian gene regulation. He delves into investigating the erasure of DNA methylation in the germline, highlighting the key role of the TET-enzymes in demethylation processes.
Dr. Hackett shares insights from his research on pluripotent stem cells, where he mapped genome-wide DNA methylation and hydroxymethylation in different pluripotent states. He discusses the impact of extrinsic conditions on pluripotent states and the biases observed in lineage preferences.
Furthermore, the discussion delves into the development of a CRISPR screening tool to study cell fate transitions, particularly focusing on the genetic factors contributing to germline specification. He also talks about his work on epigenetic inheritance, highlighting the importance of precise perturbations in understanding chromatin modifications and their functional implications.
In a recent study, the Hackett lab focuses on systematic epigenome editing to investigate the context-dependent functions of chromatin modifications. We hear about this work, and the complexity of interactions between chromatin marks, DNA sequences, and transcription factors, shedding light on the nuanced effects of various chromatin modifications on gene expression.
References* Hackett JA, Reddington JP, Nestor CE, et al. Promoter DNA methylation couples genome-defence mechanisms to epigenetic reprogramming in the mouse germline. Development (Cambridge, England). 2012 Oct;139(19):3623-3632. DOI: 10.1242/dev.081661. PMID: 22949617; PMCID: PMC3436114. * Hackett JA, Sengupta R, Zylicz JJ, et al. Germline DNA demethylation dynamics and imprint erasure through 5-hydroxymethylcytosine. Science (New York, N.Y.). 2013 Jan;339(6118):448-452. DOI: 10.1126/science.1229277. PMID: 23223451; PMCID: PMC3847602. * Hackett JA, Kobayashi T, Dietmann S, Surani MA. Activation of Lineage Regulators and Transposable Elements across a Pluripotent Spectrum. Stem Cell Reports. 2017 Jun;8(6):1645-1658. DOI: 10.1016/j.stemcr.2017.05.014. PMID: 28591649; PMCID: PMC5470235. * Hackett JA, Huang Y, Günesdogan U, et al. Tracing the transitions from pluripotency to germ cell fate with CRISPR screening. Nature Communications. 2018 Oct;9(1):4292. DOI: 10.1038/s41467-018-06230-0. PMID: 30327475; PMCID: PMC6191455.
Related Episodes* Epigenetic and Metabolic Regulation of Early Development (Jan Żylicz) * H3K79 Methylation, DOT1L, and FOXG1 in Neural Development (Tanja Vogel) * The Impact of Chromatin Modifiers on Disease Development and Progression (Capucine van Rechem)
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In this episode of the Epigenetics Podcast, we talked with Lothar Schermelleh from the University of Oxford about his work on advanced optical imaging in 3D nuclear organisation.
The interview starts by Lothar Schermelleh sharing his groundbreaking work in understanding chromatin organization using super-resolution microscopy techniques. He then delves into his past experiments, including his publication on imaging chromatin domains and X chromosome inactivation. His work showcases the power of structured illumination microscopy in overcoming diffraction limits, revealing insights into nuclear organization and regulation.
Lothar also discusses refining methods for labeling chromosome territories and replication domains, as well as exploring structural and functional nuclear organization using advanced microscopy techniques. They touch on the potential of AI in microscopy, the importance of quality control in imaging, and Lothar's grant proposal for developing artifact-free, super-resolution imaging under cryo conditions with adaptive optics.
The conversation emphasizes the intersection of technology development and biological applications, highlighting the importance of addressing specific biological questions through innovative imaging approaches.
References Schermelleh, L., Carlton, P. M., Haase, S., Shao, L., Winoto, L., Kner, P., Burke, B., Cardoso, M. C., Agard, D. A., Gustafsson, M. G., Leonhardt, H., & Sedat, J. W. (2008). Subdiffraction multicolor imaging of the nuclear periphery with 3D structured illumination microscopy. Science (New York, N.Y.), 320(5881), 1332–1336. https://doi.org/10.1126/science.1156947 * Schermelleh, L., Heintzmann, R., & Leonhardt, H. (2010). A guide to super-resolution fluorescence microscopy. The Journal of cell biology, 190(2), 165–175. https://doi.org/10.1083/jcb.201002018 * Smeets, D., Markaki, Y., Schmid, V. J., Kraus, F., Tattermusch, A., Cerase, A., Sterr, M., Fiedler, S., Demmerle, J., Popken, J., Leonhardt, H., Brockdorff, N., Cremer, T., Schermelleh, L., & Cremer, M. (2014). Three-dimensional super-resolution microscopy of the inactive X chromosome territory reveals a collapse of its active nuclear compartment harboring distinct Xist RNA foci. Epigenetics & chromatin, 7, 8. https://doi.org/10.1186/1756-8935-7-8 * Ball, G., Demmerle, J., Kaufmann, R., Davis, I., Dobbie, I. M., & Schermelleh, L. (2015). SIMcheck: a Toolbox for Successful Super-resolution Structured Illumination Microscopy. Scientific reports, 5*, 15915. https://doi.org/10.1038/srep15915
Related Episodes* Long-Range Transcriptional Control by 3D Chromosome Structure (Luca Giorgetti) * Analysis of 3D Chromatin Structure Using Super-Resolution Imaging (Alistair Boettiger)
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In this episode of the Epigenetics Podcast, we talked with Dr. Stephan Hamperl from the Helmholtz Zentrum Munich about his work on how conflicts between transcription, replication, and R-loop formation influence genome stability in human cells.
During the early stages of his career Stephan studied conflicts between transcription and replication in human cells, particularly focusing on R-loop structures. In our discussion, he explains the formation of R-loops and their impact on genome stability, emphasizing the importance of the orientation of replication forks approaching R-loops in determining DNA damage outcomes.
Stephan then delves into his work on the MATAC-Seq method, which analyzes chromatin domains at DNA replication origins to understand replication timing variability. The method involves methylating DNA linkers between nucleosomes and using nanopore sequencing for single-molecule readouts, revealing heterogeneity in chromatin structure at replication origins.
Finally, Stephan discusses his automated image analysis pipeline for quantifying transcription and replication activity overlap in mammalian genomes, addressing the challenge of visualizing these processes simultaneously. The conversation concludes with insights into Stefan's future research directions, focusing on understanding transcription-replication conflicts' molecular basis and their potential implications in cancer cell transformation.
References Hamperl, S., Brown, C. R., Garea, A. V., Perez-Fernandez, J., Bruckmann, A., Huber, K., Wittner, M., Babl, V., Stoeckl, U., Deutzmann, R., Boeger, H., Tschochner, H., Milkereit, P., & Griesenbeck, J. (2014). Compositional and structural analysis of selected chromosomal domains from Saccharomyces cerevisiae. Nucleic acids research, 42(1), e2. https://doi.org/10.1093/nar/gkt891 * Hamperl, S., Bocek, M. J., Saldivar, J. C., Swigut, T., & Cimprich, K. A. (2017). Transcription-Replication Conflict Orientation Modulates R-Loop Levels and Activates Distinct DNA Damage Responses. Cell, 170(4), 774–786.e19. https://doi.org/10.1016/j.cell.2017.07.043 * Chanou, A., Weiβ, M., Holler, K., Sajid, A., Straub, T., Krietsch, J., Sanchi, A., Ummethum, H., Lee, C. S. K., Kruse, E., Trauner, M., Werner, M., Lalonde, M., Lopes, M., Scialdone, A., & Hamperl, S. (2023). Single molecule MATAC-seq reveals key determinants of DNA replication origin efficiency. Nucleic acids research, 51*(22), 12303–12324. https://doi.org/10.1093/nar/gkad1022
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In this episode of the Epigenetics Podcast, we talked with Nadav Ahituv from University of California, San Francisco about his work on mutations of gene regulatory elements in human disease.
Using massively parallel experiments, his lab revolutionized functional genomics by studying the impact of transcription factor binding sites on gene expression. His groundbreaking technology deciphered the regulatory language of gene expression by exploring transcription factor combinations, spacing, and orientation. By delving into the influence of DNA shape and gene topology, Nadav Ahituv's research provides a comprehensive understanding of gene regulation at the molecular level, shedding light on the complexity of genetic interactions.
The conversation delves into specific cases involving enhancers, gene sequencing, and 3D genomic structure, highlighting the impact of critical elements such as CTCF sites on gene expression. Discussions of haploid insufficiency and its implications for human health, using CRISPR technology to enhance gene expression, offer new possibilities for treating genetic diseases. Explorations of leptin-responsive regulatory elements in the hypothalamus and liver-associated transcription factors provide insights into metabolic regulation and gene expression networks in different tissues.
The episode also explores the epigenomic landscape, the evolution of methods from bulk approaches to single-cell analyses, and the role of AI and machine learning in deciphering complex genetic patterns. The conversation transitions to a unique study of bat embryonic development, dietary differences, and their implications for understanding wing development and metabolism in different bat species.
References Ahituv, N., Zhu, Y., Visel, A., Holt, A., Afzal, V., Pennacchio, L. A., & Rubin, E. M. (2007). Deletion of ultraconserved elements yields viable mice. PLoS biology, 5(9), e234. https://doi.org/10.1371/journal.pbio.0050234 * Matharu, N., Rattanasopha, S., Tamura, S., Maliskova, L., Wang, Y., Bernard, A., Hardin, A., Eckalbar, W. L., Vaisse, C., & Ahituv, N. (2019). CRISPR-mediated activation of a promoter or enhancer rescues obesity caused by haploinsufficiency. Science (New York, N.Y.), 363(6424), eaau0629. https://doi.org/10.1126/science.aau0629 * Ushiki, A., Zhang, Y., Xiong, C., Zhao, J., Georgakopoulos-Soares, I., Kane, L., Jamieson, K., Bamshad, M. J., Nickerson, D. A., University of Washington Center for Mendelian Genomics, Shen, Y., Lettice, L. A., Silveira-Lucas, E. L., Petit, F., & Ahituv, N. (2021). Deletion of CTCF sites in the SHH locus alters enhancer-promoter interactions and leads to acheiropodia. Nature communications, 12(1), 2282. https://doi.org/10.1038/s41467-021-22470-z * Georgakopoulos-Soares, I., Deng, C., Agarwal, V., Chan, C. S. Y., Zhao, J., Inoue, F., & Ahituv, N. (2023). Transcription factor binding site orientation and order are major drivers of gene regulatory activity. Nature communications, 14(1), 2333. https://doi.org/10.1038/s41467-023-37960-5 * Gordon, W. E., Baek, S., Nguyen, H. P., Kuo, Y. M., Bradley, R., Fong, S. L., Kim, N., Galazyuk, A., Lee, I., Ingala, M. R., Simmons, N. B., Schountz, T., Cooper, L. N., Georgakopoulos-Soares, I., Hemberg, M., & Ahituv, N. (2024). Integrative single-cell characterization of a frugivorous and an insectivorous bat kidney and pancreas. Nature communications, 15*(1), 12. https://doi.org/10.1038/s41467-023-44186-y
Related Episodes* Ultraconserved Enhancers and Enhancer Redundancy (Diane Dickel) * Enhancers and Chromatin Remodeling in Mammary Gland Development (Camila dos Santos) * Enhancer-Promoter Interactions During Development (Yad Ghavi-Helm)
Contact* Epigenetics Podcast on X * Epigenetics Podcast on Instagram * Epigenetics Podcast on Mastodon * Epigenetics Podcast on Bluesky * Epigenetics Podcast on Threads * Active Motif on X * Active Motif on LinkedIn * Email: podcast@activemotif.com
In this episode of the Epigenetics Podcast, we talked with Ana Cvejic from the Biotech Research & Innovation Centre at the University of Copenhagen about her work on using sc-multiomics to characterise human developmental hematopoiesis.
The conversation starts by delving into Ana's research on hematopoiesis, starting with her work on identifying novel genes controlling blood traits in zebrafish models. She explains her transition to single-cell methodologies and the application of single-cell RNA sequencing to study hematopoietic cells in zebrafish, focusing on thrombocyte lineage commitment and gene expression.
The discussion progresses to her groundbreaking study on human fetal hematopoiesis, where she combined single-cell RNA-seq with single-cell ATAC-seq to understand chromatin accessibility and gene expression dynamics. Ana then shares insights into the identification of new cell surface markers and the priming of hematopoietic stem cells, particularly in conditions like Down syndrome.
Furthermore, she then elaborates on the construction of a phylogenetic tree of blood development using whole-genome sequencing of single-cell-derived hematopoietic colonies from healthy human fetuses. She explains the motivation behind this study, highlighting the insights gained regarding stem cell quantities, developmental timelines, and mutations in blood development.
References Bielczyk-Maczyńska, E., Serbanovic-Canic, J., Ferreira, L., Soranzo, N., Stemple, D. L., Ouwehand, W. H., & Cvejic, A. (2014). A loss of function screen of identified genome-wide association study Loci reveals new genes controlling hematopoiesis. PLoS genetics, 10(7), e1004450. https://doi.org/10.1371/journal.pgen.1004450 * Athanasiadis, E. I., Botthof, J. G., Andres, H., Ferreira, L., Lio, P., & Cvejic, A. (2017). Single-cell RNA-sequencing uncovers transcriptional states and fate decisions in haematopoiesis. Nature communications, 8(1), 2045. https://doi.org/10.1038/s41467-017-02305-6 * Ranzoni, A. M., Tangherloni, A., Berest, I., Riva, S. G., Myers, B., Strzelecka, P. M., Xu, J., Panada, E., Mohorianu, I., Zaugg, J. B., & Cvejic, A. (2021). Integrative Single-Cell RNA-Seq and ATAC-Seq Analysis of Human Developmental Hematopoiesis. Cell stem cell, 28*(3), 472–487.e7. https://doi.org/10.1016/j.stem.2020.11.015
Related Episodes* Single Cell Epigenomics in Neuronal Development (Tim Petros) * ATAC-Seq, scATAC-Seq and Chromatin Dynamics in Single-Cells (Jason Buenrostro) * Single-Cell Technologies using Microfluidics (Ben Hindson)
Contact* Epigenetics Podcast on X * Epigenetics Podcast on Instagram * Epigenetics Podcast on Mastodon * Epigenetics Podcast on Bluesky * Epigenetics Podcast on Threads * Active Motif on X * Active Motif on LinkedIn * Email: podcast@activemotif.com
In this episode of the Epigenetics Podcast, we talked with Sven Heinz from the University of California in San Diego about his work on the impact of sequence variation on transcription factor binding affinities and genetic diversity.
Sven Heinz talks about a landmark study published in Nature that examined the impact of sequence variation on transcription factor binding affinities and downstream effects on gene expression. Modifying genetic sequences to understand the influence of different motifs provided valuable insights into how genetic variation shapes cellular responses and gene expression patterns, underscoring the importance of genetic diversity.
Methodological approaches using inducible systems to observe changes in transcription factor binding patterns highlight the critical role of motif variation and redundancy in transcription factor families. These studies provide essential insights into the complex network of transcriptional regulation and chromatin dynamics, revealing the nuanced mechanisms that control gene expression and chromatin organization. In addition, he is investigating how small nucleotide changes can significantly affect transcription factor binding in macrophages from different mouse strains, shedding light on the intricate effects of genetic variation on transcription factor binding.
Sven's career path from project scientist to assistant professor at UC San Diego and the Salk Institute reflects a journey marked by serendipitous opportunities and a collaborative, innovative research environment. The podcast delves into the effects of influenza virus infection on chromosomal territories, gene transcription, and chromatin structure, unraveling the sophisticated interplay between viral infection and host cell transcriptional regulation.
References Heinz, S., Benner, C., Spann, N., Bertolino, E., Lin, Y. C., Laslo, P., Cheng, J. X., Murre, C., Singh, H., & Glass, C. K. (2010). Simple combinations of lineage-determining transcription factors prime cis-regulatory elements required for macrophage and B cell identities. Molecular cell, 38(4), 576–589. https://doi.org/10.1016/j.molcel.2010.05.004 * Heinz, S., Romanoski, C. E., Benner, C., Allison, K. A., Kaikkonen, M. U., Orozco, L. D., & Glass, C. K. (2013). Effect of natural genetic variation on enhancer selection and function. Nature, 503(7477), 487–492. https://doi.org/10.1038/nature12615 * Texari, L., Spann, N. J., Troutman, T. D., Sakai, M., Seidman, J. S., & Heinz, S. (2021). An optimized protocol for rapid, sensitive and robust on-bead ChIP-seq from primary cells. STAR protocols, 2*(1), 100358. https://doi.org/10.1016/j.xpro.2021.100358
Related Episodes* Pioneer Transcription Factors and Their Influence on Chromatin Structure (Ken Zaret) * Multiple Challenges in ChIP (Adam Blattler) * The Role of Pioneer Factors Zelda and Grainyhead at the Maternal-to-Zygotic Transition (Melissa Harrison)
Contact* Epigenetics Podcast on X * Epigenetics Podcast on Instagram * Epigenetics Podcast on Mastodon * Epigenetics Podcast on Bluesky * Epigenetics Podcast on Threads * Active Motif on X * Active Motif on LinkedIn * Email: podcast@activemotif.com
In this episode of the Epigenetics Podcast, we talked with Sarah Marzi from the UK Dementia Research Institute at Imperial College London about her work on epigenetic changes in Alzheimer's Disease, and comparing CUT&Tag to ENCODE ChIP-Seq using limited cell samples.
The interview discusses Sarah Marzi's work on ChIP-Seq experiments and their significance in understanding Alzheimer's disease from an epigenetic perspective. The discussion touches on the widespread dysregulation and changes in acetylation, particularly in genes associated with Alzheimer's risk, providing insights into potential links between epigenetic insults and disease onset.
Moving on to the technical aspects of the study, the interview examines the strategic use of CUT&Tag. It explores the challenges and optimizations involved in accurately profiling limited cell samples. The dialogue also compares CUT&Tag to ENCODE ChIP-Seq, highlighting the complexities of peak calling and data interpretation across different methodologies.
References Kumsta, R., Marzi, S., Viana, J. et al. Severe psychosocial deprivation in early childhood is associated with increased DNA methylation across a region spanning the transcription start site of CYP2E1. Transl Psychiatry 6, e830 (2016). https://doi.org/10.1038/tp.2016.95 * Marzi, S. J., Schilder, B. M., Nott, A., Frigerio, C. S., Willaime‐Morawek, S., Bucholc, M., Hanger, D. P., James, C., Lewis, P. A., Lourida, I., Noble, W., Rodriguez‐Algarra, F., Sharif, J., Tsalenchuk, M., Winchester, L. M., Yaman, Ü., Yao, Z., The Deep Dementia Phenotyping (DEMON) Network, Ranson, J. M., & Llewellyn, D. J. (2023). Artificial intelligence for neurodegenerative experimental models. Alzheimer’s & Dementia, 19(12), 5970–5987. https://doi.org/10.1002/alz.13479 * Marzi, S. J., Leung, S. K., Ribarska, T., Hannon, E., Smith, A. R., Pishva, E., Poschmann, J., Moore, K., Troakes, C., Al-Sarraj, S., Beck, S., Newman, S., Lunnon, K., Schalkwyk, L. C., & Mill, J. (2018). A histone acetylome-wide association study of Alzheimer’s disease identifies disease-associated H3K27ac differences in the entorhinal cortex. Nature Neuroscience, 21(11), 1618–1627. https://doi.org/10.1038/s41593-018-0253-7 * Hu, D., Abbasova, L., Schilder, B. M., Nott, A., Skene, N. G., & Marzi, S. J. (2022). CUT&Tag recovers up to half of ENCODE ChIP-seq peaks in modifications of H3K27* [Preprint]. Genomics. https://doi.org/10.1101/2022.03.30.486382
Related Episodes* When is a Peak a Peak? (Claudio Cantù) * Development of Integrative Machine Learning Tools for Neurodegenerative Diseases (Enrico Glaab) * DNA Methylation Alterations in Neurodegenerative Diseases (Paula Desplats)
Contact* Epigenetics Podcast on X * Epigenetics Podcast on Instagram * Epigenetics Podcast on Mastodon * Epigenetics Podcast on Bluesky * Epigenetics Podcast on Threads * Active Motif on X * Active Motif on LinkedIn * Email: podcast@activemotif.com
In this episode of the Epigenetics Podcast, we talked with Mark Parthun from Ohio State University about his work on the role of Hat1p in chromatin assembly.
Mark Parthun shares insights into his pivotal paper in 2004 that explored the link between type B histone acetyltransferases and chromatin assembly, setting the stage for his current research interests in epigenetics. He highlights the role of HAT1 in acetylating lysines on newly synthesized histones, its involvement in double-strand break repair, and the search for phenotypes associated with HAT1 mutations.
The discussion expands to a collaborative research project between two scientists uncovering the roles of HAT1 and NASP as chaperones in chromatin assembly. Transitioning from yeast to mouse models, the team investigated the effects of HAT1 knockout on mouse phenotypes, particularly in lung development and craniofacial morphogenesis. They also explored the impact of histone acetylation on chromatin dynamics and its influence on lifespan, aging processes, and longevity.
References Parthun, M. R., Widom, J., & Gottschling, D. E. (1996). The Major Cytoplasmic Histone Acetyltransferase in Yeast: Links to Chromatin Replication and Histone Metabolism. Cell, 87(1), 85–94. https://doi.org/10.1016/S0092-8674(00)81325-2 * Kelly, T. J., Qin, S., Gottschling, D. E., & Parthun, M. R. (2000). Type B histone acetyltransferase Hat1p participates in telomeric silencing. Molecular and cellular biology, 20(19), 7051–7058. https://doi.org/10.1128/MCB.20.19.7051-7058.2000 * Ai, X., & Parthun, M. R. (2004). The nuclear Hat1p/Hat2p complex: a molecular link between type B histone acetyltransferases and chromatin assembly. Molecular cell, 14(2), 195–205. https://doi.org/10.1016/s1097-2765(04)00184-4 * Nagarajan, P., Ge, Z., Sirbu, B., Doughty, C., Agudelo Garcia, P. A., Schlederer, M., Annunziato, A. T., Cortez, D., Kenner, L., & Parthun, M. R. (2013). Histone acetyl transferase 1 is essential for mammalian development, genome stability, and the processing of newly synthesized histones H3 and H4. PLoS genetics, 9(6), e1003518. https://doi.org/10.1371/journal.pgen.1003518 * Agudelo Garcia, P. A., Hoover, M. E., Zhang, P., Nagarajan, P., Freitas, M. A., & Parthun, M. R. (2017). Identification of multiple roles for histone acetyltransferase 1 in replication-coupled chromatin assembly. Nucleic Acids Research, 45(16), 9319–9335. https://doi.org/10.1093/nar/gkx545 * Popova, L. V., Nagarajan, P., Lovejoy, C. M., Sunkel, B. D., Gardner, M. L., Wang, M., Freitas, M. A., Stanton, B. Z., & Parthun, M. R. (2021). Epigenetic regulation of nuclear lamina-associated heterochromatin by HAT1 and the acetylation of newly synthesized histones. Nucleic Acids Research, 49*(21), 12136–12151. https://doi.org/10.1093/nar/gkab1044
Related Episodes* Regulation of Chromatin Organization by Histone Chaperones (Geneviève Almouzni) * Effects of Non-Enzymatic Covalent Histone Modifications on Chromatin (Yael David) * scDamID, EpiDamID and Lamina Associated Domains (Jop Kind)
Contact* Epigenetics Podcast on X * Epigenetics Podcast on Instagram * Epigenetics Podcast on Mastodon * Epigenetics Podcast on Bluesky * Epigenetics Podcast on Threads * Active Motif on X * Active Motif on LinkedIn * Email: podcast@activemotif.com
In this episode of the Epigenetics Podcast, we talked with Upasna Sharma from UC Santa Cruz about her work on a number of interesting projects on H2A.Z and telomeres, the impact of paternal diet on offspring metabolism, and the role of small RNAs in sperm.
In this interview Upasna Sharma discusses her work on the study of the paternal diet's impact on offspring metabolism. She reveals the discovery of small non-coding RNAs, particularly tRNA fragments, in mature mammalian sperm that may carry epigenetic information to the next generation. She explains the specific alterations in tRNA fragment levels in response to a low-protein diet and the connections found between tRNA fragments and metabolic status.
Dr. Sharma further explains the degradation and stabilization of tRNA fragments in cells and the processes involved in their regulation. She shares their observation of tRNA fragment abundance in epididymal sperm, despite the sperm being transcriptionally silent at that time. This leads to a discussion on the role of the epididymis in the reprogramming of small RNA profiles and the transportation of tRNA fragments through extracellular vesicles.
The conversation then shifts towards the potential mechanism of how environmental information could be transmitted to sperm and the observed changes in small RNAs in response to a low-protein diet. Dr. Sharma discusses the manipulation of small RNAs in embryos and mouse embryonic stem cells, revealing their role in regulating specific sets of genes during early development. However, the exact mechanisms that link these early changes to metabolic phenotypes are still being explored.
References Sharma, U., Conine, C. C., Shea, J. M., Boskovic, A., Derr, A. G., Bing, X. Y., Belleannee, C., Kucukural, A., Serra, R. W., Sun, F., Song, L., Carone, B. R., Ricci, E. P., Li, X. Z., Fauquier, L., Moore, M. J., Sullivan, R., Mello, C. C., Garber, M., & Rando, O. J. (2016). Biogenesis and function of tRNA fragments during sperm maturation and fertilization in mammals. Science (New York, N.Y.), 351(6271), 391–396. https://doi.org/10.1126/science.aad6780 * Sharma, U., Sun, F., Conine, C. C., Reichholf, B., Kukreja, S., Herzog, V. A., Ameres, S. L., & Rando, O. J. (2018). Small RNAs Are Trafficked from the Epididymis to Developing Mammalian Sperm. Developmental cell, 46(4), 481–494.e6. https://doi.org/10.1016/j.devcel.2018.06.023 * Rinaldi, V. D., Donnard, E., Gellatly, K., Rasmussen, M., Kucukural, A., Yukselen, O., Garber, M., Sharma, U., & Rando, O. J. (2020). An atlas of cell types in the mouse epididymis and vas deferens. eLife, 9*, e55474. https://doi.org/10.7554/eLife.55474
Related Episodes The Epigenetics of Human Sperm Cells (Sarah Kimmins) * Transgenerational Inheritance and Evolution of Epimutations (Peter Sarkies) * The Role of Small RNAs in Transgenerational Inheritance in C. elegans* (Oded Rechavi)
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In this episode of the Epigenetics Podcast, we talked with Weiwei Dang from Baylor College of Medicine about his work on molecular mechanisms of aging and the role of H3K36me3 and cryptic transcription in cellular aging.
The team in the Weiwei Dang lab explored the connection between histone marks, specifically H4K16 acetylation and H3K36 methylation, and aging. Dr. Dang describes how the lab conducted experiments by mutating H4K16 to determine its effect on lifespan. They observed that the mutation to glutamine accelerated the aging process and shortened lifespan, providing causal evidence for the relationship between H4K16 and lifespan. They also discovered that mutations in acetyltransferase and demethylase enzymes had opposite effects on lifespan, further supporting a causal relationship.
Weiwei Dang then discusses their expanded research on aging, conducting high-throughput screens to identify other histone residues and mutants in yeast that regulate aging. They found that most mutations at K36 shortened lifespan, and so they decided to follow up on a site that is known to be methylated and play a role in gene function. They discovered that H3K36 methylation helps suppress cryptic transcription, which is transcription that initiates from within the gene rather than at the promoter. Mutants lacking K36 methylation showed an aging phenotype. They also found evidence of cryptic transcription in various datasets related to aging and senescence, including C. elegans and mammalian cells.
References
- Dang, W., Steffen, K., Perry, R. et al. Histone H4 lysine 16 acetylation regulates cellular lifespan. Nature 459, 802–807 (2009). https://doi.org/10.1038/nature08085
- Sen, P., Dang, W., Donahue, G., Dai, J., Dorsey, J., Cao, X., Liu, W., Cao, K., Perry, R., Lee, J. Y., Wasko, B. M., Carr, D. T., He, C., Robison, B., Wagner, J., Gregory, B. D., Kaeberlein, M., Kennedy, B. K., Boeke, J. D., & Berger, S. L. (2015). H3K36 methylation promotes longevity by enhancing transcriptional fidelity. Genes & development, 29(13), 1362–1376. https://doi.org/10.1101/gad.263707.115
- Yu, R., Cao, X., Sun, L. et al. Inactivating histone deacetylase HDA promotes longevity by mobilizing trehalose metabolism. Nat Commun 12, 1981 (2021). https://doi.org/10.1038/s41467-021-22257-2
- McCauley, B.S., Sun, L., Yu, R. et al. Altered chromatin states drive cryptic transcription in aging mammalian stem cells. Nat Aging 1, 684–697 (2021). https://doi.org/10.1038/s43587-021-00091-x
Related Episodes
- Epigenetic Mechanisms of Aging and Longevity (Shelley Berger)
- Epigenetic Clocks and Biomarkers of Ageing (Morgan Levine)
- Gene Dosage Alterations in Evolution and Ageing (Claudia Keller Valsecchi)
Contact* Epigenetics Podcast on X * Epigenetics Podcast on Instagram * Epigenetics Podcast on Mastodon * Epigenetics Podcast on Bluesky * Epigenetics Podcast on Threads * Active Motif on X * Active Motif on LinkedIn * Email: podcast@activemotif.com
In this episode of the Epigenetics Podcast, we talked with Mitch Guttman from California Institute of Technology about his work on characterising the 3D interactions of the genome using Split-Pool Recognition of Interactions by Tag Extension (SPRITE).
Mitch Guttman discusses his exploration of the long non-coding RNA Xist, which plays a crucial role in X chromosome inactivation. He explains how they discovered that Xist is present everywhere in the nucleus, not just in specific locations on the X chromosome. Through their research, they identified critical proteins like SHARP that are involved in X chromosome silencing.
The discussion then shifts to SPRITE, a method they developed to map multi-way contacts and generalize beyond DNA to include RNA and proteins. They compare SPRITE to classical proximity ligation methods like Hi-C and discuss how cluster sizes in SPRITE can estimate 3D distances between molecules. The conversation also touches upon the potential of applying SPRITE to single-cell experiments, allowing for the mapping of higher order nucleic acid interactions and tracking the connectivity of DNA fragments in individual cells.
References Jesse M. Engreitz et al., The Xist lncRNA Exploits Three-Dimensional Genome Architecture to Spread Across the X Chromosome. Science 341,1237973(2013). DOI:10.1126/science.1237973 * Chun-Kan Chen et al., Xist recruits the X chromosome to the nuclear lamina to enable chromosome-wide silencing. Science 354, 468-472(2016). DOI: 10.1126/science.aae0047 * Quinodoz, S. A., Ollikainen, N., Tabak, B., Palla, A., Schmidt, J. M., Detmar, E., Lai, M. M., Shishkin, A. A., Bhat, P., Takei, Y., Trinh, V., Aznauryan, E., Russell, P., Cheng, C., Jovanovic, M., Chow, A., Cai, L., McDonel, P., Garber, M., & Guttman, M. (2018). Higher-Order Inter-chromosomal Hubs Shape 3D Genome Organization in the Nucleus. Cell, 174(3), 744-757.e24. https://doi.org/10.1016/j.cell.2018.05.024 * Goronzy, I. N., Quinodoz, S. A., Jachowicz, J. W., Ollikainen, N., Bhat, P., & Guttman, M. (2022). Simultaneous mapping of 3D structure and nascent RNAs argues against nuclear compartments that preclude transcription. Cell Reports, 41(9), 111730. https://doi.org/10.1016/j.celrep.2022.111730 * Perez, A. A., Goronzy, I. N., Blanco, M. R., Guo, J. K., & Guttman, M. (2023). ChIP-DIP: A multiplexed method for mapping hundreds of proteins to DNA uncovers diverse regulatory elements controlling gene expression* [Preprint]. Genomics. https://doi.org/10.1101/2023.12.14.571730
Related Episodes* Epigenetics and X-Inactivation (Edith Heard) * Hi-C and Three-Dimensional Genome Sequencing (Erez Lieberman Aiden) * Unraveling Mechanisms of Chromosome Formation (Job Dekker)
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In this episode of the Epigenetics Podcast, we talked with Yali Dou from Keck School of Medicine of USC about her work on MLL Proteins in Mixed-Lineage Leukemia.
To start off this Interview Yali describes her early work on MLL1 and its function in transcription, particularly its involvement in histone modification. She explains her successful purification of the MLL complex and the discovery of MOF as one of the proteins involved.
Next, the interview focuses on her work in reconstituting the MLL core complex and the insights gained from this process. She shares her experience of reconstituting the MLL complex and discusses her focus on the crosstalk of H3K4 and H3K79 methylation, regulated by H2BK34 ubiquitination.
The podcast then delves into the therapeutic potential of MLL1, leading to the discovery of a small molecule inhibitor. Finally, we talk about the importance of the protein WDR5 in the assembly of MLL complexes and how targeting the WDR5-ML interaction can inhibit MLL activity.
References Dou, Y., Milne, T., Ruthenburg, A. et al. Regulation of MLL1 H3K4 methyltransferase activity by its core components. Nat Struct Mol Biol 13, 713–719 (2006). https://doi.org/10.1038/nsmb1128 * Wu, L., Zee, B. M., Wang, Y., Garcia, B. A., & Dou, Y. (2011). The RING Finger Protein MSL2 in the MOF Complex Is an E3 Ubiquitin Ligase for H2B K34 and Is Involved in Crosstalk with H3 K4 and K79 Methylation. Molecular Cell, 43(1), 132–144. https://doi.org/10.1016/j.molcel.2011.05.015 * Cao, F., Townsend, E. C., Karatas, H., Xu, J., Li, L., Lee, S., Liu, L., Chen, Y., Ouillette, P., Zhu, J., Hess, J. L., Atadja, P., Lei, M., Qin, Z. S., Malek, S., Wang, S., & Dou, Y. (2014). Targeting MLL1 H3K4 Methyltransferase Activity in Mixed-Lineage Leukemia. Molecular Cell, 53(2), 247–261. https://doi.org/10.1016/j.molcel.2013.12.001 * Park, S.H., Ayoub, A., Lee, YT. et al. Cryo-EM structure of the human MLL1 core complex bound to the nucleosome. Nat Commun* 10, 5540 (2019). https://doi.org/10.1038/s41467-019-13550-2
Related Episodes* Dosage Compensation in Drosophila (Asifa Akhtar) * Targeting COMPASS to Cure Childhood Leukemia (Ali Shilatifard)
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In this episode of the Epigenetics Podcast, we talked with Sam Buckberry from the Telethon Kids Institute about his work on gene imprinting, sex-biased gene expression, DNA regulatory landscapes, and genomics in the indigenous population of Australia.
Sam Buckberry's research career started with working on the imprinting of H19, IGF2, and IGF2R genes in the placenta. We talk about the controversy surrounding the imprinting of IGF2R and how his study used pyrosequencing to quantify gene expression. We also discuss Sam's work on sex-biased gene expression in the placenta and the identification of a cluster of genes related to placental development and pregnancy.
In addition, we talk about Sam's research on reprogramming and the characterization of DNA regulatory landscapes during the process. We discuss the challenges of working with sequencing data, the discovery of epigenetic memories, and erasing them during reprogramming. Towards the end of the conversation, Sam mentions his current work in setting up an epigenetics group focused on indigenous genomics. They are conducting a large-scale, multi-omics study on cardiometabolic conditions in samples from indigenous Australian communities, with the goal of identifying biomarkers and better understanding the molecular basis of these conditions.
References Buckberry, S., Liu, X., Poppe, D. et al. Transient naive reprogramming corrects hiPS cells functionally and epigenetically. Nature* 620, 863–872 (2023). https://doi.org/10.1038/s41586-023-06424-7 * Knaupp AS1, Buckberry S1, Pflueger J, Lim SM, Ford E, Larcombe MR, Rossello FJ, de Mendoza A, Alaei S, Firas J, Holmes ML, Nair SS, Clark SJ, Nefzger CM, Lister R and Polo JM (2017). Transient and permanent reconfiguration of chromatin and transcription factor occupancy drive reprogramming. Cell Stem Cell 21, 1-12 1 Co-first author
Related Episodes* The Effect of Mechanotransduction on Chromatin Structure and Transcription in Stem Cells (Sara Wickström) * Differential Methylated Regions in Autism Spectrum Disorders (Janine La Salle) * The Role of Pioneer Factors Zelda and Grainyhead at the Maternal-to-Zygotic Transition (Melissa Harrison)
Contact* Epigenetics Podcast on X * Epigenetics Podcast on Instagram * Epigenetics Podcast on Mastodon * Epigenetics Podcast on Bluesky * Epigenetics Podcast on Threads * Active Motif on X * Active Motif on LinkedIn * Email: podcast@activemotif.com
In this episode of the Epigenetics Podcast, we talked with Kyle Eagen from Baylor College of Medicine about his work on BET Proteins and their role in chromosome folding and compartmentalization.
In the early days of his research career Dr. Eagen made use of genomics and microscopy to study chromosomes, particularly polytene chromosomes in Drosophila. The correlation between the folding patterns detected by Hi-C and polytene bands highlights the similarities between the two, bridging traditional cytology with modern NGS methods. This work formed the basis of Kyle's thesis and sparked his interest in nuclear organization and chromosome 3D structure.
In his independent lab Kyle then studied compartments in chromatin structure and focused on the relationship between histone modifications and the 3D structure of chromosomes. The discovery of BRD4-NUT, a fusion oncoprotein that reprograms chromosome 3D structure, is highlighted as a significant step forward in understanding chromatin structure.
The conversation then shifts to the use of a tool to test hypotheses about the involvement of BRD4 in a specific process, leading to consistent results and considerations for manipulating chromosome organization for therapeutic purposes. The role of BET proteins in genome folding and the need for further research on other factors involved in 3D genome structure are discussed.
References Rosencrance, C. D., Ammouri, H. N., Yu, Q., Ge, T., Rendleman, E. J., Marshall, S. A., & Eagen, K. P. (2020). Chromatin Hyperacetylation Impacts Chromosome Folding by Forming a Nuclear Subcompartment. Molecular Cell, 78(1), 112-126.e12. https://doi.org/10.1016/j.molcel.2020.03.018 * Huang, Y., Durall, R. T., Luong, N. M., Hertzler, H. J., Huang, J., Gokhale, P. C., Leeper, B. A., Persky, N. S., Root, D. E., Anekal, P. V., Montero Llopis, P. D. L. M., David, C. N., Kutok, J. L., Raimondi, A., Saluja, K., Luo, J., Zahnow, C. A., Adane, B., Stegmaier, K., … French, C. A. (2023). EZH2 Cooperates with BRD4-NUT to Drive NUT Carcinoma Growth by Silencing Key Tumor Suppressor Genes. Cancer Research, 83*(23), 3956–3973. https://doi.org/10.1158/0008-5472.CAN-23-1475
Related Episodes* Hi-C and Three-Dimensional Genome Sequencing (Erez Lieberman Aiden) * Genome Organization Mediated by RNA Polymerase II (Argyrys Papantonis) * Analysis of 3D Chromatin Structure Using Super-Resolution Imaging (Alistair Boettiger)
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In this episode of the Epigenetics Podcast, we talked with Francesca Telese from UC San Diego and Jessica Zhou from Cold Spring Harbour about their work on the molecular underpinnings of human addiction.
Francesca Telese worked on neuronal enhancers and their pivotal role in governing gene activity. She sheds light on her remarkable findings concerning the epigenetic signature of neuronal enhancers that are intricately involved in synaptic plasticity.
Jessica Zhou joined Francesca Telese's lab as a PhD student where she worked on elucidating the effects of chronic cannabis use on memory and behavior in mice. She takes us through the fascinating correlation between THC and gene co-expression networks. Francesca and Jessicathen discuss the utilization of genetically diverse outbred rats in their research, along with the crucial exploration of cell type specificity in gene expression studies. They then delve into the long-term changes that occur in the brain after drug exposure and the profound implications for relapse. Additionally, they touch upon the challenges they face in analyzing single-cell data.
References Zhou, J. L., de Guglielmo, G., Ho, A. J., Kallupi, M., Pokhrel, N., Li, H. R., Chitre, A. S., Munro, D., Mohammadi, P., Carrette, L. L. G., George, O., Palmer, A. A., McVicker, G., & Telese, F. (2023). Single-nucleus genomics in outbred rats with divergent cocaine addiction-like behaviors reveals changes in amygdala GABAergic inhibition. Nature neuroscience, https://doi.org/10.1038/s41593-023-01452-y * Wang, J., Telese, F., Tan, Y., Li, W., Jin, C., He, X., Basnet, H., Ma, Q., Merkurjev, D., Zhu, X., Liu, Z., Zhang, J., Ohgi, K., Taylor, H., White, R. R., Tazearslan, C., Suh, Y., Macfarlan, T. S., Pfaff, S. L., & Rosenfeld, M. G. (2015). LSD1n is an H4K20 demethylase regulating memory formation via transcriptional elongation control. Nature neuroscience, 18*(9), 1256–1264. https://doi.org/10.1038/nn.4069
Related Episodes* The Role of Histone Dopaminylation and Serotinylation in Neuronal Plasticity (Ian Maze)
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In this episode of the Epigenetics Podcast, we talked with Tanja Vogel from the University Clinics Freiburg about her work on epigenetic modifications in stem cells during central nervous system development.
During our discussion, Dr. Vogel shared that she and her team have investigated H3K79 methylation and its functional significance, which remains a topic of debate in the scientific community. They’ve also investigated the role of DOT1L in neural development and its implications for neuronal networks, as disrupting DOT1L can lead to conditions such as epilepsy and schizophrenia. They explored the function of the SOX2 enhancer in the presence or absence of DOT1L enzymatic inhibition.
The conversation then shifts to FoxG1, a vital player in forebrain development. The team uncovered its role in chromatin accessibility and its connection to microRNA processing. Their study, utilizing ChIP-Seq, reveals FoxG1's interactions with enhancer regions and other transcription factors, like NeuroD1.
References
- Britanova, O., de Juan Romero, C., Cheung, A., Kwan, K. Y., Schwark, M., Gyorgy, A., Vogel, T., Akopov, S., Mitkovski, M., Agoston, D., Sestan, N., Molnár, Z., & Tarabykin, V. (2008). Satb2 is a postmitotic determinant for upper-layer neuron specification in the neocortex. Neuron, 57(3), 378–392. https://doi.org/10.1016/j.neuron.2007.12.028
- Büttner, N., Johnsen, S. A., Kügler, S., & Vogel, T. (2010). Af9/Mllt3 interferes with Tbr1 expression through epigenetic modification of histone H3K79 during development of the cerebral cortex. Proceedings of the National Academy of Sciences of the United States of America, 107(15), 7042–7047. https://doi.org/10.1073/pnas.0912041107
- Franz, H., Villarreal, A., Heidrich, S., Videm, P., Kilpert, F., Mestres, I., Calegari, F., Backofen, R., Manke, T., & Vogel, T. (2019). DOT1L promotes progenitor proliferation and primes neuronal layer identity in the developing cerebral cortex. Nucleic acids research, 47(1), 168–183. https://doi.org/10.1093/nar/gky953
- Ferrari, F., Arrigoni, L., Franz, H., Izzo, A., Butenko, L., Trompouki, E., Vogel, T., & Manke, T. (2020). DOT1L-mediated murine neuronal differentiation associates with H3K79me2 accumulation and preserves SOX2-enhancer accessibility. Nature communications, 11(1), 5200. https://doi.org/10.1038/s41467-020-19001-7
- Akol, I., Izzo, A., Gather, F., Strack, S., Heidrich, S., Ó hAilín, D., Villarreal, A., Hacker, C., Rauleac, T., Bella, C., Fischer, A., Manke, T., & Vogel, T. (2023). Multimodal epigenetic changes and altered NEUROD1 chromatin binding in the mouse hippocampus underlie FOXG1 syndrome. Proceedings of the National Academy of Sciences of the United States of America, 120(2), e2122467120. https://doi.org/10.1073/pnas.2122467120
Related Episodes* Molecular Mechanisms of Chromatin Modifying Enzymes (Karim-Jean Armache)
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In this episode of the Epigenetics Podcast, we talked with Maria Gambetta from the University of Lausanne about her work on the function of insulators in 3D genome folding.
Maria Gambetta focuses on investigating 3D contact dynamics between enhancers and promoters, providing insights into tissue-specific gene activation. The team used capture-C to analyze dynamic looping events, emphasizing the significance of accessible chromatin peaks in enhancer-promoter interactions. Furthermore, they focused on gene insulation and CTCF's role in forming topologically associating domains in Drosophila. Hi-C analysis on CTCF mutants revealed the conservation of TAD boundary mechanisms, identifying CP-190 as a potential binding protein.
Their findings on the loss of TAD boundaries in mutants and the role of transcription in TAD boundary formation are discussed as well as the function of CP190 and insulators in preventing interactions between promoters and enhancers. Their work challenges existing models of insulator function and seeks to understand their mechanisms better. The conversation concludes with insights into long-range regulatory associations in Drosophila, emphasizing the punctual interactions between transcription factor binding sites and their effect on neural gene transcription and genome folding.
References
- Gambetta, M. C., Oktaba, K., & Müller, J. (2009). Essential role of the glycosyltransferase sxc/Ogt in polycomb repression. Science (New York, N.Y.), 325(5936), 93–96. https://doi.org/10.1126/science.1169727
- Kaushal, A., Mohana, G., Dorier, J., Özdemir, I., Omer, A., Cousin, P., Semenova, A., Taschner, M., Dergai, O., Marzetta, F., Iseli, C., Eliaz, Y., Weisz, D., Shamim, M. S., Guex, N., Lieberman Aiden, E., & Gambetta, M. C. (2021). CTCF loss has limited effects on global genome architecture in Drosophila despite critical regulatory functions. Nature communications, 12(1), 1011. https://doi.org/10.1038/s41467-021-21366-2
- Hoencamp, C., Dudchenko, O., Elbatsh, A. M. O., Brahmachari, S., Raaijmakers, J. A., van Schaik, T., Sedeño Cacciatore, Á., Contessoto, V. G., van Heesbeen, R. G. H. P., van den Broek, B., Mhaskar, A. N., Teunissen, H., St Hilaire, B. G., Weisz, D., Omer, A. D., Pham, M., Colaric, Z., Yang, Z., Rao, S. S. P., Mitra, N., … Rowland, B. D. (2021). 3D genomics across the tree of life reveals condensin II as a determinant of architecture type. Science (New York, N.Y.), 372(6545), 984–989. https://doi.org/10.1126/science.abe2218
- Mohana, G., Dorier, J., Li, X., Mouginot, M., Smith, R. C., Malek, H., Leleu, M., Rodriguez, D., Khadka, J., Rosa, P., Cousin, P., Iseli, C., Restrepo, S., Guex, N., McCabe, B. D., Jankowski, A., Levine, M. S., & Gambetta, M. C. (2023). Chromosome-level organization of the regulatory genome in the Drosophila nervous system. Cell, 186(18), 3826–3844.e26. https://doi.org/10.1016/j.cell.2023.07.008
Related Episodes
- Hi-C and Three-Dimensional Genome Sequencing (Erez Lieberman Aiden)
- Biophysical Modeling of 3-D Genome Organization (Leonid Mirny)
- Long-Range Transcriptional Control by 3D Chromosome Structure (Luca Giorgetti)
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In this episode of the Epigenetics Podcast, we talked with Jason Carroll from the Cambridge Research Institute about his work on contribution of estrogen receptor to breast cancer progression.
The Podcast centers around the crucial role of the forkhead protein FOXA1 in breast cancer. FOXA1 acts as a pioneer transcription factor, facilitating gene regulation by recruiting nuclear receptors to chromatin, profoundly influencing gene expression in various breast cancer subtypes. The FOXA1-positive subtype of triple-negative breast cancer, despite being estrogen receptor-negative, shares gene expression profiles with estrogen receptor-positive breast cancer, shedding light on the importance of targeting the androgen receptor for treatment.
The challenges of studying transcription factor mappings from clinical samples are explored, with a focus on the ChIP-seq method's success in mapping estrogen receptor binding sites. Various techniques for transcription factor mapping, including CUT&RUN, CUT&Tag, and ChIP-exo, are discussed, as well as the potential of mass spec techniques like the RIME method in analyzing protein interactions. An intriguing experiment involving the purification of multiple proteins to identify interactions is highlighted.
References
- Carroll, J. S., Meyer, C. A., Song, J., Li, W., Geistlinger, T. R., Eeckhoute, J., Brodsky, A. S., Keeton, E. K., Fertuck, K. C., Hall, G. F., Wang, Q., Bekiranov, S., Sementchenko, V., Fox, E. A., Silver, P. A., Gingeras, T. R., Liu, X. S., & Brown, M. (2006). Genome-wide analysis of estrogen receptor binding sites. Nature genetics, 38(11), 1289–1297. https://doi.org/10.1038/ng1901
- Hurtado, A., Holmes, K. A., Geistlinger, T. R., Hutcheson, I. R., Nicholson, R. I., Brown, M., Jiang, J., Howat, W. J., Ali, S., & Carroll, J. S. (2008). Regulation of ERBB2 by oestrogen receptor-PAX2 determines response to tamoxifen. Nature, 456(7222), 663–666. https://doi.org/10.1038/nature07483
- Ross-Innes, C. S., Stark, R., Teschendorff, A. E., Holmes, K. A., Ali, H. R., Dunning, M. J., Brown, G. D., Gojis, O., Ellis, I. O., Green, A. R., Ali, S., Chin, S. F., Palmieri, C., Caldas, C., & Carroll, J. S. (2012). Differential oestrogen receptor binding is associated with clinical outcome in breast cancer. Nature, 481(7381), 389–393. https://doi.org/10.1038/nature10730
- Mohammed, H., Russell, I. A., Stark, R., Rueda, O. M., Hickey, T. E., Tarulli, G. A., Serandour, A. A., Birrell, S. N., Bruna, A., Saadi, A., Menon, S., Hadfield, J., Pugh, M., Raj, G. V., Brown, G. D., D'Santos, C., Robinson, J. L., Silva, G., Launchbury, R., Perou, C. M., … Carroll, J. S. (2015). Progesterone receptor modulates ERα action in breast cancer. Nature, 523(7560), 313–317. https://doi.org/10.1038/nature14583
Related Episodes
- Pioneer Transcription Factors and Their Influence on Chromatin Structure (Ken Zaret)
- The Role of Pioneer Factors Zelda and Grainyhead at the Maternal-to-Zygotic Transition (Melissa Harrison)
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In this episode of the Epigenetics Podcast, we caught up with Sheila Teves from the University of British Columbia to talk about her work on the inheritance of transcriptional memory by mitotic bookmarking.
Early in her research career, Sheila Teves focused on the impact of nucleosomes on torsional stress and gene regulation. She also highlights the development of a genome-wide approach to measure torsional stress and its relationship to nucleosome dynamics and RNA polymerase regulation.
The conversation then shifts to her focus on transcriptional memory and mitotic bookmarking during her postdoc in the Tijan lab. She explores the concept of mitotic bookmarking, whereby certain transcription factors remain bound to their target sites during mitosis, facilitating efficient reactivation of transcription after cell division. She discusses her findings on the behavior of transcription factors on mitotic chromosomes, challenging the notion that they are excluded during mitosis. She also discusses the differences in binding behavior between the general transcription factor TBP and other transcription factors. Finally, the effect of formaldehyde fixation on the potential to find transcription factors bound to mitotic chromosomes is discussed.
References Teves, S., Henikoff, S. Transcription-generated torsional stress destabilizes nucleosomes. Nat Struct Mol Biol 21, 88–94 (2014). https://doi.org/10.1038/nsmb.2723 * Sheila S Teves, Luye An, Anders S Hansen, Liangqi Xie, Xavier Darzacq, Robert Tjian (2016) A dynamic mode of mitotic bookmarking by transcription factors eLife 5:e22280. https://doi.org/10.7554/eLife.22280 * Sheila S Teves, Luye An, Aarohi Bhargava-Shah, Liangqi Xie, Xavier Darzacq, Robert Tjian (2018) A stable mode of bookmarking by TBP recruits RNA polymerase II to mitotic chromosomes eLife 7:e35621. https://doi.org/10.7554/eLife.35621 * Kwan, J. Z. J., Nguyen, T. F., Uzozie, A. C., Budzynski, M. A., Cui, J., Lee, J. M. C., Van Petegem, F., Lange, P. F., & Teves, S. S. (2023). RNA Polymerase II transcription independent of TBP in murine embryonic stem cells. eLife, 12, e83810. https://doi.org/10.7554/eLife.83810 * Price, R. M., Budzyński, M. A., Shen, J., Mitchell, J. E., Kwan, J. Z. J., & Teves, S. S. (2023). Heat shock transcription factors demonstrate a distinct mode of interaction with mitotic chromosomes. Nucleic acids research, 51*(10), 5040–5055. https://doi.org/10.1093/nar/gkad304
Related Episodes In Vivo* Nucleosome Structure and Dynamics (Srinivas Ramachandran) * From Nucleosome Structure to Function (Karolin Luger) * Structural Analysis of Nucleosomes During Transcription (Lucas Farnung)
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In this episode of the Epigenetics Podcast, we talked with Janine La Salle from UC Davis about her work on differential methylated regions in autism spectrum disorders.
In our discussion, Janine LaSalle highlights her work on the placental epigenetic signature, which offers insights into the impact of fetal exposures and gene-environment interactions during the perinatal period. She emphasizes the placenta's value as a surrogate tissue for understanding human diseases. Her research on DNA methylation in the placenta across different mammalian species reveals consistent patterns in partially methylated and highly methylated domains. She explains the critical role of higher methylation levels in specific regions for gene expression and how this knowledge helps trace the placenta's developmental history.
The conversation then delves into Dr. LaSalle's research on the link between placental DNA methylation and autism. Through epigenome-wide association studies, she discovered a novel autism gene and explored the effects of prenatal exposures on DNA methylation profiles. Additionally, she discusses the impact of maternal obesity on offspring neurodevelopment. Ultimately, the goal of her research is to contribute to precision public health and preventative healthcare with epigenetic signatures offering high potential for predicting and preventing future health problems.
References
- Schroeder, D. I., Blair, J. D., Lott, P., Yu, H. O., Hong, D., Crary, F., Ashwood, P., Walker, C., Korf, I., Robinson, W. P., & LaSalle, J. M. (2013). The human placenta methylome. Proceedings of the National Academy of Sciences of the United States of America, 110(15), 6037–6042. https://doi.org/10.1073/pnas.1215145110
- Zhu, Y., Gomez, J. A., Laufer, B. I., Mordaunt, C. E., Mouat, J. S., Soto, D. C., Dennis, M. Y., Benke, K. S., Bakulski, K. M., Dou, J., Marathe, R., Jianu, J. M., Williams, L. A., Gutierrez Fugón, O. J., Walker, C. K., Ozonoff, S., Daniels, J., Grosvenor, L. P., Volk, H. E., Feinberg, J. I., … LaSalle, J. M. (2022). Placental methylome reveals a 22q13.33 brain regulatory gene locus associated with autism. Genome biology, 23(1), 46. https://doi.org/10.1186/s13059-022-02613-1
- Laufer, B. I., Hasegawa, Y., Zhang, Z., Hogrefe, C. E., Del Rosso, L. A., Haapanen, L., Hwang, H., Bauman, M. D., Van de Water, J., Taha, A. Y., Slupsky, C. M., Golub, M. S., Capitanio, J. P., VandeVoort, C. A., Walker, C. K., & LaSalle, J. M. (2022). Multi-omic brain and behavioral correlates of cell-free fetal DNA methylation in macaque maternal obesity models. Nature communications, 13(1), 5538. https://doi.org/10.1038/s41467-022-33162-7
- Coulson, R. L., Yasui, D. H., Dunaway, K. W., Laufer, B. I., Vogel Ciernia, A., Zhu, Y., Mordaunt, C. E., Totah, T. S., & LaSalle, J. M. (2018). Snord116-dependent diurnal rhythm of DNA methylation in mouse cortex. Nature communications, 9(1), 1616. https://doi.org/10.1038/s41467-018-03676-0
- Neier, K., Grant, T. E., Palmer, R. L., Chappell, D., Hakam, S. M., Yasui, K. M., Rolston, M., Settles, M. L., Hunter, S. S., Madany, A., Ashwood, P., Durbin-Johnson, B., LaSalle, J. M., & Yasui, D. H. (2021). Sex disparate gut microbiome and metabolome perturbations precede disease progression in a mouse model of Rett syndrome. Communications biology, 4(1), 1408. https://doi.org/10.1038/s42003-021-02915-3
Related Episodes
- DNA Methylation Alterations in Neurodegenerative Diseases (Paula Desplats)
- Characterization of Epigenetic States in the Oligodendrocyte Lineage (Gonçalo Castelo-Branco)
- The Role of Histone Dopaminylation and Serotinylation in Neuronal Plasticity (Ian Maze)
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In this episode of the Epigenetics Podcast, we caught up with Björn Schumacher from the Institute for Genome Stability in Ageing and Disease at the University of Cologne to talk about his work on DNA damage in longevity and ageing.
In this episode Björn Schumacher discusses his research on DNA repair and its impact on ageing. We explore his insights on the effects of DNA damage on transcription, the importance of studying development, and the role of histone modifications. We also discuss paternal DNA damage inheritance and the DREAM complex as a master regulator of DNA repair. The lab’s goal is to enhance somatic DNA repair for healthier ageing and disease prevention.
References
- Schumacher, B., van der Pluijm, I., Moorhouse, M. J., Kosteas, T., Robinson, A. R., Suh, Y., Breit, T. M., van Steeg, H., Niedernhofer, L. J., van Ijcken, W., Bartke, A., Spindler, S. R., Hoeijmakers, J. H., van der Horst, G. T., & Garinis, G. A. (2008). Delayed and accelerated aging share common longevity assurance mechanisms. PLoS genetics, 4(8), e1000161. https://doi.org/10.1371/journal.pgen.1000161
- Ermolaeva, M. A., Segref, A., Dakhovnik, A., Ou, H. L., Schneider, J. I., Utermöhlen, O., Hoppe, T., & Schumacher, B. (2013). DNA damage in germ cells induces an innate immune response that triggers systemic stress resistance. Nature, 501(7467), 416–420. https://doi.org/10.1038/nature12452
- Wang, S., Meyer, D. H., & Schumacher, B. (2023). Inheritance of paternal DNA damage by histone-mediated repair restriction. Nature, 613(7943), 365–374. https://doi.org/10.1038/s41586-022-05544-w
- Bujarrabal-Dueso, A., Sendtner, G., Meyer, D. H., Chatzinikolaou, G., Stratigi, K., Garinis, G. A., & Schumacher, B. (2023). The DREAM complex functions as conserved master regulator of somatic DNA-repair capacities. Nature structural & molecular biology, 30(4), 475–488. https://doi.org/10.1038/s41594-023-00942-8
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- Epigenetic Clocks and Biomarkers of Ageing (Morgan Levine)
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In this episode of the Epigenetics Podcast, we talked with Capucine van Rechem from Stanford University about her work on the impact of chromatin modifiers on disease development and progression.
During her postdoctoral work, Capucine van Rechem studied the effects of Single nucleotide polymorphisms (SNPs) in KDM4A on lung cancer cell lines and discovered a link between KDM4A and mTOR. She found that cells with the SNP had decreased KDM4A levels and increased sensitivity to inhibitors of the translation pathway. In addition, she found that a combination of histone marks was more predictive of replication timing than RNA expression alone, and identified the specific stages of the cell cycle where KDM4 primarily acts.
Now in her own lab, the focus of her work shifted to SWI-SNF. The team has discovered the role of SWI-SNF in translation through polysome profiling and confirmed the interaction between SWI-SNF and translation. They are currently working to understand the functions of different complexes in translation and their connection to transcription.
References
- Black, J. C., Manning, A. L., Van Rechem, C., Kim, J., Ladd, B., Cho, J., Pineda, C. M., Murphy, N., Daniels, D. L., Montagna, C., Lewis, P. W., Glass, K., Allis, C. D., Dyson, N. J., Getz, G., & Whetstine, J. R. (2013). KDM4A lysine demethylase induces site-specific copy gain and rereplication of regions amplified in tumors. Cell, 154(3), 541–555. https://doi.org/10.1016/j.cell.2013.06.051
- Van Rechem, C., Ji, F., Mishra, S., Chakraborty, D., Murphy, S. E., Dillingham, M. E., Sadreyev, R. I., & Whetstine, J. R. (2020). The lysine demethylase KDM4A controls the cell-cycle expression of replicative canonical histone genes. Biochimica et biophysica acta. Gene regulatory mechanisms, 1863(10), 194624. https://doi.org/10.1016/j.bbagrm.2020.194624
- Van Rechem, C., Ji, F., Chakraborty, D., Black, J. C., Sadreyev, R. I., & Whetstine, J. R. (2021). Collective regulation of chromatin modifications predicts replication timing during cell cycle. Cell reports, 37(1), 109799. https://doi.org/10.1016/j.celrep.2021.109799
- Ulicna, L., Kimmey, S. C., Weber, C. M., Allard, G. M., Wang, A., Bui, N. Q., Bendall, S. C., Crabtree, G. R., Bean, G. R., & Van Rechem, C. (2022). The Interaction of SWI/SNF with the Ribosome Regulates Translation and Confers Sensitivity to Translation Pathway Inhibitors in Cancers with Complex Perturbations. Cancer research, 82(16), 2829–2837. https://doi.org/10.1158/0008-5472.CAN-21-1360
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In this episode of the Epigenetics Podcast, we caught up with Luca Giorgetti from the Friedrich Miescher Institute to hear about his work on long-range transcriptional control by 3D chromosome structure.
Luca Giorgetti's research focuses on chromosomal interactions, transcriptional output, and the dynamics of enhancer-promoter relationships. His lab investigated the causal relationship between chromosome interactions and transcriptional events. They’ve found that by manipulating the contact probabilities between an enhancer and a promoter by changing their distance, these changes had a substantial effect on transcription levels. This project was an experiment that Luca Giorgetti was eager to do, and it allowed him to establish a smooth functional relationship between contact probabilities and changes in transcription levels.
References
- Giorgetti, L., Galupa, R., Nora, E. P., Piolot, T., Lam, F., Dekker, J., Tiana, G., & Heard, E. (2014). Predictive polymer modeling reveals coupled fluctuations in chromosome conformation and transcription. Cell, 157(4), 950–963. https://doi.org/10.1016/j.cell.2014.03.025
- Redolfi, J., Zhan, Y., Valdes-Quezada, C., Kryzhanovska, M., Guerreiro, I., Iesmantavicius, V., Pollex, T., Grand, R. S., Mulugeta, E., Kind, J., Tiana, G., Smallwood, S. A., de Laat, W., & Giorgetti, L. (2019). DamC reveals principles of chromatin folding in vivo without crosslinking and ligation. Nature structural & molecular biology, 26(6), 471–480. https://doi.org/10.1038/s41594-019-0231-0
- Zuin, J., Roth, G., Zhan, Y., Cramard, J., Redolfi, J., Piskadlo, E., Mach, P., Kryzhanovska, M., Tihanyi, G., Kohler, H., Eder, M., Leemans, C., van Steensel, B., Meister, P., Smallwood, S., & Giorgetti, L. (2022). Nonlinear control of transcription through enhancer-promoter interactions. Nature, 604(7906), 571–577. https://doi.org/10.1038/s41586-022-04570-y
- Mach, P., Kos, P. I., Zhan, Y., Cramard, J., Gaudin, S., Tünnermann, J., Marchi, E., Eglinger, J., Zuin, J., Kryzhanovska, M., Smallwood, S., Gelman, L., Roth, G., Nora, E. P., Tiana, G., & Giorgetti, L. (2022). Cohesin and CTCF control the dynamics of chromosome folding. Nature genetics, 54(12), 1907–1918. https://doi.org/10.1038/s41588-022-01232-7
Related Episodes
- scDamID, EpiDamID and Lamina Associated Domains (Jop Kind)
- Epigenetics and X-Inactivation (Edith Heard)
- Spatial Organization of the Human Genome (Wendy Bickmore)
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In this episode of the Epigenetics Podcast, we talked with Mary Gehring from MIT about her work on transgenerational inheritance and epigenetic imprinting in plants.
Mary Gehring and her team are focusing on plant epigenetics and genetic imprinting in plants by studying DNA methylation in Arabidopsis. They have found significant differences in DNA methylation between the embryo and endosperm of plants, particularly in relation to imprinted genes. We also discuss their work on hydroxymethylcytosine (5-hmC) in Arabidopsis and the challenges of detecting and studying this epigenetic modification.
Next, we discuss the regulatory circuit involving ROS1, a DNA glycosylase involved in demethylation, and its role in maintaining epigenetic homeostasis. The interview concludes with a discussion of CUT&RUN, which the lab has adapted for use in plants. Due to its low input requirements this method has been valuable in studying various plant tissues and has influenced Mary Gehring's research on imprinting in Arabidopsis endosperm.
References
- Gehring, M., Bubb, K. L., & Henikoff, S. (2009). Extensive demethylation of repetitive elements during seed development underlies gene imprinting. Science (New York, N.Y.), 324(5933), 1447–1451. https://doi.org/10.1126/science.1171609
- Pignatta, D., Erdmann, R. M., Scheer, E., Picard, C. L., Bell, G. W., & Gehring, M. (2014). Natural epigenetic polymorphisms lead to intraspecific variation in Arabidopsis gene imprinting. eLife, 3, e03198. https://doi.org/10.7554/eLife.03198
- Klosinska, M., Picard, C. L., & Gehring, M. (2016). Conserved imprinting associated with unique epigenetic signatures in the Arabidopsis genus. Nature plants, 2, 16145. https://doi.org/10.1038/nplants.2016.145
- Zheng, X. Y., & Gehring, M. (2019). Low-input chromatin profiling in Arabidopsis endosperm using CUT&RUN. Plant reproduction, 32(1), 63–75. https://doi.org/10.1007/s00497-018-00358-1
Related Episodes
- The Role of Small RNAs in Transgenerational Inheritance in C. elegans (Oded Rechavi)
- Epigenetic Influence on Memory Formation and Inheritance (Isabelle Mansuy)
- The Epigenetics of Human Sperm Cells (Sarah Kimmins)
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In this episode of the Epigenetics Podcast, we talked to Claudio Cantù from Linköping University about his work on peak blacklists, peak concordance and what is a peak in CUT&RUN.
Our host Stefan Dillinger and guest Claudio Cantù dive into the topic of when we can be sure that a peak is a peak. To help with this, Claudio Cantù's group has been working on defining a set of suspicious peaks that can be used as a "peak blacklist" and can be subtracted to clean up CUT&RUN data sets. The lab also worked on a method called ICEBERG (Increased Capture of Enrichment By Exhaustive Replicate aGgregation) to help define peaks from a number of experimental replicates. By using this algorithm, the team is trying to discover the beta-catenin binding profile, not the tip of the beta-catenin binding iceberg, but the whole of the beta-catenin binding profile.
References
- Zambanini, G., Nordin, A., Jonasson, M., Pagella, P., & Cantù, C. (2022). A new CUT&RUN low volume-urea (LoV-U) protocol optimized for transcriptional co-factors uncovers Wnt/β-catenin tissue-specific genomic targets. Development (Cambridge, England), 149(23), dev201124. https://doi.org/10.1242/dev.201124
- Nordin, A., Zambanini, G., Pagella, P., & Cantù, C. (2022). The CUT&RUN Blacklist of Problematic Regions of the Genome [Preprint]. Genomics. https://doi.org/10.1101/2022.11.11.516118
- Nordin, A., Pagella, P., Zambanini, G., & Cantu, C. (2023). Exhaustive identification of genome-wide binding events of transcriptional regulators with ICEBERG [Preprint]. Genomics. https://doi.org/10.1101/2023.06.29.547050
Related Episodes
- Chromatin Profiling: From ChIP to CUT&RUN, CUT&Tag and CUTAC (Steven Henikoff)
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Single Cell Epigenomics in Neuronal Development (Tim Petros)
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In this episode of the Epigenetics Podcast, we talked with Alistair Boettiger from Stanford University about his work on the analysis of 3D chromatin structure of single cells using super-resolution imaging.
Alistair Boettiger and his team focus on developing advanced microscopy techniques to understand gene regulation at the level of 3D genome organization. They have developed Optical Reconstruction of Chromatin Architecture (ORCA), a microscopy approach to trace the 3-dimensional DNA path in the nucleus with genomic resolution down to 2 kb and a throughput of ~10,000 cells per experiment. These methods enable the identification of structural features with comparable resolution to Hi-C, while the advantages of microscopy such as single cell resolution and multimodal measurements remain.
References
- Boettiger, A., Bintu, B., Moffitt, J. et al. Super-resolution imaging reveals distinct chromatin folding for different epigenetic states. Nature 529, 418–422 (2016). https://doi.org/10.1038/nature16496
- Bogdan Bintu et al., Super-resolution chromatin tracing reveals domains and cooperative interactions in single cells. Science 362, eaau1783 (2018). DOI:10.1126/science.aau1783
- Mateo, L.J., Sinnott-Armstrong, N. & Boettiger, A.N. Tracing DNA paths and RNA profiles in cultured cells and tissues with ORCA. Nat Protoc 16, 1647–1713 (2021). https://doi.org/10.1038/s41596-020-00478-x
- Rajpurkar, A.R., Mateo, L.J., Murphy, S.E. et al. Deep learning connects DNA traces to transcription to reveal predictive features beyond enhancer–promoter contact. Nat Commun 12, 3423 (2021). https://doi.org/10.1038/s41467-021-23831-4
- Tzu-Chiao Hung, David M. Kingsley, & Alistair Boettiger. (2023). Boundary stacking interactions enable cross-TAD enhancer-promoter communication during limb development. BioRxiv, 2023.02.06.527380. https://doi.org/10.1101/2023.02.06.527380
- Hafner, A., Park, M., Berger, S. E., Murphy, S. E., Nora, E. P., & Boettiger, A. N. (2023). Loop stacking organizes genome folding from TADs to chromosomes. Molecular cell, 83(9), 1377–1392.e6. https://doi.org/10.1016/j.molcel.2023.04.008
Related Episodes
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- Unraveling Mechanisms of Chromosome Formation (Job Dekker)
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Biophysical Modeling of 3-D Genome Organization (Leonid Mirny)
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In this episode of the Epigenetics Podcast, we caught up with Claudia Keller Valsecchi from the Institute for Molecular Biology in Mainz to talk about her work on gene dosage alterations in evolution and ageing.
Claudia Keller-Valsecchi's team focuses on understanding the fundamental mechanisms of how cellular function in eukaryotes is influenced by gene copy number variation. Recent findings indicate that precise MSL2-mediated gene dosage is highly relevant for organismal development. Since 2020 Claudia Keller-Valsecchi runs her own lab at the IMB in Mainz, Germany, where she tries to understand from a molecular mechanistic point of view how gene dosage compensation works, with projects in mosquitoes and in Artemia franciscanagene, as well as dosage regulation in the mammalian system regarding development and disease.
References
- Keller, C., Adaixo, R., Stunnenberg, R., Woolcock, K. J., Hiller, S., & Bühler, M. (2012). HP1Swi6 Mediates the Recognition and Destruction of Heterochromatic RNA Transcripts. Molecular Cell, 47(2), 215–227. https://doi.org/10.1016/j.molcel.2012.05.009
- Valsecchi, C.I.K., Basilicata, M.F., Georgiev, P. et al. RNA nucleation by MSL2 induces selective X chromosome compartmentalization. Nature 589, 137–142 (2021). https://doi.org/10.1038/s41586-020-2935-z
- Keller Valsecchi, C. I., Marois, E., Basilicata, M. F., Georgiev, P., & Akhtar, A. (2021). Distinct mechanisms mediate X chromosome dosage compensation in Anopheles and Drosophila. Life Science Alliance, 4(9), e202000996. https://doi.org/10.26508/lsa.202000996
Related Episodes
- Epigenetics and X-Inactivation (Edith Heard)
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Dosage Compensation in Drosophila (Asifa Akhtar)
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In this episode of the Epigenetics Podcast, we caught up with Lucas Farnung from Harvard Medical School to talk about his work on the structural analysis of nucleosomes during transcription.
Lucas Farnung started his scientific career in Patrick Cramer's lab, trying to solve the crystal structure of RNA polymerase II transcribing through a nucleosome. This project spanned some time before being published in 2022, during which time Dr. Farnung accomplished several other goals. The team solved the cryo-electron microscopy structure of Chd1 from the yeast Saccharomyces cerevisiae bound to a nucleosome at a resolution of 4.8 Å, solved the structure of the nucleosome-CHD4 chromatin remodeler, and investigated the structural basis of nucleosome transcription mediated by Chd1 and FACT. In 2020, he started his own lab and is now working on structural analysis of nucleosomes during transcription and how chromatin remodelers work on the chromatin template.
References
- Farnung, L., Vos, S. M., Wigge, C., & Cramer, P. (2017). Nucleosome-Chd1 structure and implications for chromatin remodelling. Nature, 550(7677), 539–542. https://doi.org/10.1038/nature24046
- Farnung, L., Vos, S. M., & Cramer, P. (2018). Structure of transcribing RNA polymerase II-nucleosome complex. Nature communications, 9(1), 5432. https://doi.org/10.1038/s41467-018-07870-y
- Filipovski, M., Soffers, J. H. M., Vos, S. M., & Farnung, L. (2022). Structural basis of nucleosome retention during transcription elongation. Science (New York, N.Y.), 376(6599), 1313–1316. https://doi.org/10.1126/science.abo3851
Related Episodes
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From Nucleosome Structure to Function (Karolin Luger)
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In this episode of the Epigenetics Podcast, we caught up with Paula Desplats from the University of California San Diego to talk about her work on DNA Methylation Alterations in Neurodegenerative Diseases.
The laboratory of Paula desalts focuses on decoding the role of epigenetic mechanisms, like DNA methylation, on the onset and progression of neurodegenerative diseases like Parkinson’s and Alzheimer’s. In doing so, on of the goals of the Desplats team is to develop a biomarker panel based on quantification of DNA methylation of selected genes that can discriminate Parkison's Disease patients from healthy subjects in a simple blood test. More recently, the team also focused on the role of the circadian rhythm on neurodegenerative diseases and finding a way how interventions can help in managing the disease.
References
- Masliah, E., Dumaop, W., Galasko, D., & Desplats, P. (2013). Distinctive patterns of DNA methylation associated with Parkinson disease: identification of concordant epigenetic changes in brain and peripheral blood leukocytes. Epigenetics, 8(10), 1030–1038. https://doi.org/10.4161/epi.25865
- Cronin, P., McCarthy, M. J., Lim, A., Salmon, D. P., Galasko, D., Masliah, E., De Jager, P. L., Bennett, D. A., & Desplats, P. (2017). Circadian alterations during early stages of Alzheimer's disease are associated with aberrant cycles of DNA methylation in BMAL1. Alzheimer's & dementia : the journal of the Alzheimer's Association, 13(6), 689–700. https://doi.org/10.1016/j.jalz.2016.10.003
- Henderson-Smith, A., Fisch, K. M., Hua, J., Liu, G., Ricciardelli, E., Jepsen, K., Huentelman, M., Stalberg, G., Edland, S. D., Scherzer, C. R., Dunckley, T., & Desplats, P. (2019). DNA methylation changes associated with Parkinson's disease progression: outcomes from the first longitudinal genome-wide methylation analysis in blood. Epigenetics, 14(4), 365–382. https://doi.org/10.1080/15592294.2019.1588682
- Nasamran, C. A., Sachan, A., Mott, J., Kuras, Y. I., Scherzer, C. R., Study, H. B., Ricciardelli, E., Jepsen, K., Edland, S. D., Fisch, K. M., & Desplats, P. (2021). Differential blood DNA methylation across Lewy body dementias. Alzheimer's & dementia (Amsterdam, Netherlands), 13(1), e12156. https://doi.org/10.1002/dad2.12156
Related Episodes
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In this episode of the Epigenetics Podcast, we caught up with Jop Kind from Hubrecht Institute to talk about his work on single cell DamID, EpiDamID, and Lamina Associated Domains (LADs).
Jop Kind started out developing single cell DamID (scDamID), based on the DamID technique. First, this technique was adapted to a microscopic readout which enabled them to follow the localisation of chromatin domains after cell division. Next, the lab expanded this technique into the NGS space and created genome-wide maps of nuclear lamina Interactions in single human cells. Since LADs are in a heterochromatic chromatin context, the lab expanded scDamID into the epigenetic space. They first combined it with a transcriptional readout. Later-on they developed EpiDamID, a method to target a diverse set of chromatin types by taking advantage of the binding specificities of single-chain variable fragment antibodies, engineered chromatin reader domains, and endogenous chromatin-binding proteins.
References
- Kind, J., Pagie, L., Ortabozkoyun, H., Boyle, S., de Vries, S. S., Janssen, H., Amendola, M., Nolen, L. D., Bickmore, W. A., & van Steensel, B. (2013). Single-Cell Dynamics of Genome-Nuclear Lamina Interactions. Cell, 153(1), 178–192. https://doi.org/10.1016/j.cell.2013.02.028
- Kind, J., Pagie, L., de Vries, S. S., Nahidiazar, L., Dey, S. S., Bienko, M., Zhan, Y., Lajoie, B., de Graaf, C. A., Amendola, M., Fudenberg, G., Imakaev, M., Mirny, L. A., Jalink, K., Dekker, J., van Oudenaarden, A., & van Steensel, B. (2015). Genome-wide Maps of Nuclear Lamina Interactions in Single Human Cells. Cell, 163(1), 134–147. https://doi.org/10.1016/j.cell.2015.08.040
- Borsos, M., Perricone, S.M., Schauer, T. et al. Genome–lamina interactions are established de novo in the early mouse embryo. Nature 569, 729–733 (2019). https://doi.org/10.1038/s41586-019-1233-0
- Markodimitraki, C. M., Rang, F. J., Rooijers, K., de Vries, S. S., Chialastri, A., de Luca, K. L., Lochs, S. J. A., Mooijman, D., Dey, S. S., & Kind, J. (2020). Simultaneous quantification of protein–DNA interactions and transcriptomes in single cells with scDam&T-seq. Nature Protocols, 15(6), 1922–1953. https://doi.org/10.1038/s41596-020-0314-8
- Rang, F. J., de Luca, K. L., de Vries, S. S., Valdes-Quezada, C., Boele, E., Nguyen, P. D., Guerreiro, I., Sato, Y., Kimura, H., Bakkers, J., & Kind, J. (2022). Single-cell profiling of transcriptome and histone modifications with EpiDamID. Molecular Cell, 82(10), 1956-1970.e14. https://doi.org/10.1016/j.molcel.2022.03.009
Related Episodes
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- Single Cell Epigenomics in Neuronal Development (Tim Petros)
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In this episode of the Epigenetics Podcast, we caught up with Charlotte Proudhon from the Institut Curie to talk about her work on circulating tumor DNA and circulating Epi-mutations as biomarkers in cancer.
Charlotte Proudhon started out her research career by investigating circulating tumor DNA (ctDNA). This kind of DNA is shed into the bloodstream by apoptotic tumor cells and can be analyzed after collection by a simple blood draw, which makes it a very useful biomarker for cancer. Using this approach cancers can be identified by their unique mutational fingerprint. However, soon the limitations of this approach became apparent and the fact that this ctDNA is actually shed into the bloodstream as nucleosomal particles was utilized by the Proudhon team and now the methylation fingerprint of the LINE-1 repeats is used as a biomarker for cancer diagnosis and monitoring of the success of a cancer treatment.
References
- Decraene, C., Silveira, A. B., Bidard, F. C., Vallée, A., Michel, M., Melaabi, S., Vincent-Salomon, A., Saliou, A., Houy, A., Milder, M., Lantz, O., Ychou, M., Denis, M. G., Pierga, J. Y., Stern, M. H., & Proudhon, C. (2018). Multiple Hotspot Mutations Scanning by Single Droplet Digital PCR. Clinical chemistry, 64(2), 317–328. https://doi.org/10.1373/clinchem.2017.272518
- Bortolini Silveira, A., Bidard, F. C., Tanguy, M. L., Girard, E., Trédan, O., Dubot, C., Jacot, W., Goncalves, A., Debled, M., Levy, C., Ferrero, J. M., Jouannaud, C., Rios, M., Mouret-Reynier, M. A., Dalenc, F., Hego, C., Rampanou, A., Albaud, B., Baulande, S., Berger, F., … Pierga, J. Y. (2021). Multimodal liquid biopsy for early monitoring and outcome prediction of chemotherapy in metastatic breast cancer. NPJ breast cancer, 7(1), 115. https://doi.org/10.1038/s41523-021-00319-4
Related Episodes
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In this episode of the Epigenetics Podcast, we caught up with Luciano Di Croce from the Center of Genomic Regulation in Barcelona to talk about his work on epigenetic landscapes in cancer.
The Di Croce Lab focuses on the Polycomb Complex and its influence on diseases like cancer. Luciano Di Croce started out his research career investigating the oncogenic transcription factor PML-RAR. They could show that in leukemic cells knockdown of SUZ12, a key component of Polycomb repressive complex 2 (PRC2), reverts not only histone modification but also induces DNA de-methylation of PML-RAR target genes. More recently the team focused on two other Polycomb related proteins Zrf1 and PHF19 and were able to characterize some of their functions in gene targeting in different disease and developmental contexts.
References
- Di Croce, L., Raker, V. A., Corsaro, M., Fazi, F., Fanelli, M., Faretta, M., Fuks, F., Lo Coco, F., Kouzarides, T., Nervi, C., Minucci, S., & Pelicci, P. G. (2002). Methyltransferase recruitment and DNA hypermethylation of target promoters by an oncogenic transcription factor. Science (New York, N.Y.), 295(5557), 1079–1082. https://doi.org/10.1126/science.1065173
- Richly, H., Rocha-Viegas, L., Ribeiro, J. D., Demajo, S., Gundem, G., Lopez-Bigas, N., Nakagawa, T., Rospert, S., Ito, T., & Di Croce, L. (2010). Transcriptional activation of polycomb-repressed genes by ZRF1. Nature, 468(7327), 1124–1128. https://doi.org/10.1038/nature09574
- Jain, P., Ballare, C., Blanco, E., Vizan, P., & Di Croce, L. (2020). PHF19 mediated regulation of proliferation and invasiveness in prostate cancer cells. eLife, 9, e51373. https://doi.org/10.7554/eLife.51373
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- Targeting COMPASS to Cure Childhood Leukemia (Ali Shilatifard)
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In this episode of the Epigenetics Podcast, we caught up with Ines Drinnenberg from Institute Curie to talk about her work on the formation of CenH3-deficient kinetochores.
The laboratory of Ines Drinneberg focuses on centromeres and how different strategies of centromere organization have evolved in different organisms. While most eukaryotes have monocentric chromosomes, where spindle attachment is restricted to a single chromosomal region resembling such classic X-shape like structures under the microscope, many lineages have evolved holocentric chromosomes where spindle microtubules attach along the entire length of the chromosome. The team was able to show the independent loss of CENH3/CENP-A in holocentric insects. Furthermore, the team focuses on how CenH3-deficient kinetochores form and were able to identify several conserved kinetochore components that emerged as a key component for CenH3-deficient kinetochore formation in Lepidoptera.
References
- Drinnenberg, I. A., deYoung, D., Henikoff, S., & Malik, H. S. (2014). Recurrent loss of CenH3 is associated with independent transitions to holocentricity in insects. eLife, 3, e03676. https://doi.org/10.7554/eLife.03676
- Molaro, A., & Drinnenberg, I. A. (2018). Studying the Evolution of Histone Variants Using Phylogeny. Methods in molecular biology (Clifton, N.J.), 1832, 273–291. https://doi.org/10.1007/978-1-4939-8663-7_15
- Cortes-Silva, N., Ulmer, J., Kiuchi, T., Hsieh, E., Cornilleau, G., Ladid, I., Dingli, F., Loew, D., Katsuma, S., & Drinnenberg, I. A. (2020). CenH3-Independent Kinetochore Assembly in Lepidoptera Requires CCAN, Including CENP-T. Current biology : CB, 30(4), 561–572.e10. https://doi.org/10.1016/j.cub.2019.12.014
- Senaratne, A. P., Muller, H., Fryer, K. A., Kawamoto, M., Katsuma, S., & Drinnenberg, I. A. (2021). Formation of the CenH3-Deficient Holocentromere in Lepidoptera Avoids Active Chromatin. Current biology : CB, 31(1), 173–181.e7. https://doi.org/10.1016/j.cub.2020.09.078
- Vanpoperinghe, L., Carlier-Grynkorn, F., Cornilleau, G., Kusakabe, T., Drinnenberg, I. A., & Tran, P. T. (2021). Live-cell imaging reveals square shape spindles and long mitosis duration in the silkworm holocentric cells. microPublication biology, 2021, 10.17912/micropub.biology.000441. https://doi.org/10.17912/micropub.biology.000441
Related Episodes
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In this episode of the Epigenetics Podcast, we caught up with Paul Shiels from the University of Glasgow to talk about his work on the effects of environmental cues on the epigenome and longevity.
Paul Shiels and his team focus on the question on how age related health is influenced by the environment. Factors like the socio-economic position, nutrition, lifestyle and the environment can influence the microbiome and the inflammation burden on the body which in turn can alter individual trajectories of ageing and health. The lab also tries to understand the epigenetic, molecular and cellular mechanisms that link the exposome to chronic age related diseases of older people. They have shown that (1) imbalanced nutrition is associated with a microbiota-mediated accelerated ageing in the general population, (2) a significantly higher abundance of circulatory pathogenic bacteria is found in the most biologically aged, while those less biologically aged possess more circulatory salutogenic bacteria with a capacity to metabolise and produce cytoprotective Nrf2 agonists, (3) those at lower socioeconomic position possess significantly lower betaine levels indicative of a poorer diet and poorer health span and consistent with reduced global DNA methylation levels in this group.
References
- Harris, S. E., Deary, I. J., MacIntyre, A., Lamb, K. J., Radhakrishnan, K., Starr, J. M., Whalley, L. J., & Shiels, P. G. (2006). The association between telomere length, physical health, cognitive ageing, and mortality in non-demented older people. Neuroscience Letters, 406(3), 260–264. https://doi.org/10.1016/j.neulet.2006.07.055
- Paul G. Shiels, Improving Precision in Investigating Aging: Why Telomeres Can Cause Problems, The Journals of Gerontology: Series A, Volume 65A, Issue 8, August 2010, Pages 789–791, https://doi.org/10.1093/gerona/glq095
- Mafra D, Ugochukwu SA, Borges NA, et al. Food for healthier aging: power on your plate. Critical Reviews in Food Science and Nutrition. 2022 Aug:1-14. DOI: 10.1080/10408398.2022.2107611. PMID: 35959705.
- Shiels PG, Stenvinkel P, Kooman JP, McGuinness D. Circulating markers of ageing and allostatic load: A slow train coming. Practical Laboratory Medicine. 2017 Apr;7:49-54. DOI: 10.1016/j.plabm.2016.04.002. PMID: 28856219; PMCID: PMC5574864.
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In this episode of the Epigenetics Podcast, we caught up with Sarah Kimmins from Université de Montreal to talk about her work on the epigenetics of human sperm cells.
The focus of Sarah Kimmins and her lab is how sperm and offspring health is impacted by the father's environment. The core of this is the sperm epigenome, which has been implicated in complex diseases such as infertility, cancer, diabetes, schizophrenia and autism. The Kimmins lab is interested which players play a role in this and came across the Histone post-translational modification H3K4me3. In this interview we talk about how the father's life choices can impact offspring health, which can also be inherited transgenerationally and how this can be used to develop intervention strategies to improve child and adult health.
References
- Siklenka, K., Erkek, S., Godmann, M., Lambrot, R., McGraw, S., Lafleur, C., Cohen, T., Xia, J., Suderman, M., Hallett, M., Trasler, J., Peters, A. H., & Kimmins, S. (2015). Disruption of histone methylation in developing sperm impairs offspring health transgenerationally. Science (New York, N.Y.), 350(6261), aab2006. https://doi.org/10.1126/science.aab2006
- Lismer, A., Siklenka, K., Lafleur, C., Dumeaux, V., & Kimmins, S. (2020). Sperm histone H3 lysine 4 trimethylation is altered in a genetic mouse model of transgenerational epigenetic inheritance. Nucleic acids research, 48(20), 11380–11393. https://doi.org/10.1093/nar/gkaa712
- Lismer, A., Dumeaux, V., Lafleur, C., Lambrot, R., Brind'Amour, J., Lorincz, M. C., & Kimmins, S. (2021). Histone H3 lysine 4 trimethylation in sperm is transmitted to the embryo and associated with diet-induced phenotypes in the offspring. Developmental cell, 56(5), 671–686.e6. https://doi.org/10.1016/j.devcel.2021.01.014
Related Episodes
- H3K4me3, SET Proteins, Isw1, and their Role in Transcription (Jane Mellor)
- The Effects of Early Life Stress on Mammalian Development (Catherine J. Peña)
- DNA Methylation and Mammalian Development (Déborah Bourc'his)
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In this episode of the Epigenetics Podcast, we caught up with Peter Sarkies from London Institute of Medical Sciences to talk about his work on Transgenerational Inheritance of Epimutations.
The team in the Sarkies lab focuses on investigating the connections between epigenetic gene regulation and evolution. The lab performs evolution experiments in the nematode C. elegans to determine if evolution can be influenced by epigenetic differences between individuals in a given population when no changes in the underlying DNA sequence are observed. A second area of interest of the team is evolution of piRNAs, which are present in metazoans but have been lost in nematodes during evolution.
References
- The Selfish Gene
- Sarkies, P., & Miska, E. A. (2013). Is There Social RNA? Science, 341(6145), 467–468. https://doi.org/10.1126/science.1243175
- Beltran, T., Shahrezaei, V., Katju, V., & Sarkies, P. (2020). Epimutations driven by small RNAs arise frequently but most have limited duration in Caenorhabditis elegans. Nature ecology & evolution, 4(11), 1539–1548. https://doi.org/10.1038/s41559-020-01293-z
- Beltran, T., Pahita, E., Ghosh, S., Lenhard, B., & Sarkies, P. (2021). Integrator is recruited to promoter-proximally paused RNA Pol II to generate Caenorhabditis elegans piRNA precursors. The EMBO journal, 40(5), e105564. https://doi.org/10.15252/embj.2020105564
Related Episodes
- The Role of Small RNAs in Transgenerational Inheritance in C. elegans (Oded Rechavi)
- Epigenetic Influence on Memory Formation and Inheritance (Isabelle Mansuy)
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In this episode of the Epigenetics Podcast, we caught up with Karen Arndt from the University of Pittsburgh to talk about her work on transcription elongation control by the Paf1 complex.
Karen Arndt and her lab investigate the process of transcriptional elongation and how RNA polymerase II overcomes obstacles like nucleosomes. One of the proteins that helps overcome those obstacles is the Paf1 complex. This complex associates with the transcribing polymerase and helps in modifying the chromatin template by ubiquitinating Histone H2B and methylating Histone H3.
References
- Squazzo, S. L., Costa, P. J., Lindstrom, D. L., Kumer, K. E., Simic, R., Jennings, J. L., Link, A. J., Arndt, K. M., & Hartzog, G. A. (2002). The Paf1 complex physically and functionally associates with transcription elongation factors in vivo. The EMBO journal, 21(7), 1764–1774. https://doi.org/10.1093/emboj/21.7.1764
- Van Oss, S. B., Shirra, M. K., Bataille, A. R., Wier, A. D., Yen, K., Vinayachandran, V., Byeon, I. L., Cucinotta, C. E., Héroux, A., Jeon, J., Kim, J., VanDemark, A. P., Pugh, B. F., & Arndt, K. M. (2016). The Histone Modification Domain of Paf1 Complex Subunit Rtf1 Directly Stimulates H2B Ubiquitylation through an Interaction with Rad6. Molecular cell, 64(4), 815–825. https://doi.org/10.1016/j.molcel.2016.10.008
- Cucinotta, C. E., Hildreth, A. E., McShane, B. M., Shirra, M. K., & Arndt, K. M. (2019). The nucleosome acidic patch directly interacts with subunits of the Paf1 and FACT complexes and controls chromatin architecture in vivo. Nucleic acids research, 47(16), 8410–8423. https://doi.org/10.1093/nar/gkz549
- Hildreth, A. E., Ellison, M. A., Francette, A. M., Seraly, J. M., Lotka, L. M., & Arndt, K. M. (2020). The nucleosome DNA entry-exit site is important for transcription termination and prevention of pervasive transcription. eLife, 9, e57757. https://doi.org/10.7554/eLife.57757
Related Episodes
- Targeting COMPASS to Cure Childhood Leukemia (Ali Shilatifard)
- H3K4me3, SET Proteins, Isw1, and their Role in Transcription (Jane Mellor)
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In this episode of the Epigenetics Podcast, we caught up with Karim-Jean Armache from New York University - Grossman School of Medicine to talk about his work on the structural analysis of Polycomb Complex Proteins.
Karim-Jean Armache started his research career with the structural characterization of the 12-subunit RNA Polymerase II. After starting his own lab he used this knowledge in x-ray crystallography and electron microscopy to study how gene silencing complexes like the PRC complex act on chromatin and influence transcription. Further work in the Armache Lab focused on Dot, a histone H3K79 methyltransferase, and how it acts on chromatin, as well as how it is regulated by Histone-Histone crosstalk.
References Armache, K. J., Garlick, J. D., Canzio, D., Narlikar, G. J., & Kingston, R. E. (2011). Structural basis of silencing: Sir3 BAH domain in complex with a nucleosome at 3.0 Å resolution. Science (New York, N.Y.), 334(6058), 977–982. https://doi.org/10.1126/science.1210915 * Lee, C. H., Holder, M., Grau, D., Saldaña-Meyer, R., Yu, J. R., Ganai, R. A., Zhang, J., Wang, M., LeRoy, G., Dobenecker, M. W., Reinberg, D., & Armache, K. J. (2018). Distinct Stimulatory Mechanisms Regulate the Catalytic Activity of Polycomb Repressive Complex 2. Molecular cell, 70(3), 435–448.e5. https://doi.org/10.1016/j.molcel.2018.03.019 * De Ioannes, P., Leon, V. A., Kuang, Z., Wang, M., Boeke, J. D., Hochwagen, A., & Armache, K. J. (2019). Structure and function of the Orc1 BAH-nucleosome complex. Nature communications, 10(1), 2894. https://doi.org/10.1038/s41467-019-10609-y * Valencia-Sánchez, M. I., De Ioannes, P., Wang, M., Truong, D. M., Lee, R., Armache, J. P., Boeke, J. D., & Armache, K. J. (2021). Regulation of the Dot1 histone H3K79 methyltransferase by histone H4K16 acetylation. Science (New York, N.Y.), 371*(6527), eabc6663. https://doi.org/10.1126/science.abc6663
Related Episodes* Transcription and Polycomb in Inheritance and Disease (Danny Reinberg) * From Nucleosome Structure to Function (Karolin Luger) * Oncohistones as Drivers of Pediatric Brain Tumors (Nada Jabado)
Contact* Epigenetics Podcast on Twitter * Epigenetics Podcast on Instagram * Epigenetics Podcast on Mastodon * Active Motif on Twitter * Active Motif on LinkedIn * eMail: podcast@activemotif.com
In this episode of the Epigenetics Podcast, we caught up with Sarah Kinkley from the Max Planck Institute of Molecular Genetics to talk about her work on PHF13 and its role in chromatin and transcription.
The Kinkley laboratory focuses mainly on unraveling the mechanism of action of the transcription factor PHF13 (PHC Finger Protein 13). PHF13 is a reader of the epigenetic mark H3K4 trimethylation which influences higher chromatin order, transcriptional regulation, and differentiation. The lab has shown that PHF13 plays a crucial role in phase separation and mitotic chromatin compaction.
References
- Kinkley, S., Staege, H., Mohrmann, G., Rohaly, G., Schaub, T., Kremmer, E., Winterpacht, A., & Will, H. (2009). SPOC1: a novel PHD-containing protein modulating chromatin structure and mitotic chromosome condensation. Journal of cell science, 122(Pt 16), 2946–2956. https://doi.org/10.1242/jcs.047365
- Chung, H. R., Xu, C., Fuchs, A., Mund, A., Lange, M., Staege, H., Schubert, T., Bian, C., Dunkel, I., Eberharter, A., Regnard, C., Klinker, H., Meierhofer, D., Cozzuto, L., Winterpacht, A., Di Croce, L., Min, J., Will, H., & Kinkley, S. (2016). PHF13 is a molecular reader and transcriptional co-regulator of H3K4me2/3. eLife, 5, e10607. https://doi.org/10.7554/eLife.10607
- Connecting the Dots: PHF13 and cohesin promote polymer-polymer phase separation of chromatin into chromosomes. Francesca Rossi, Rene Buschow, Laura V. Glaser, Tobias Schubert, Hannah Staege, Astrid Grimme, Hans Will, Thorsten Milke, Martin Vingron, Andrea M. Chiariello, Sarah Kinkley. bioRxiv 2022.03.04.482956; doi: https://doi.org/10.1101/2022.03.04.482956
Related Episodes
- The Role of Blimp-1 in Immune-Cell Differentiation (Erna Magnúsdóttir)
- H3K4me3, SET Proteins, Isw1, and their Role in Transcription (Jane Mellor)
- The Role of SMCHD1 in Development and Disease (Marnie Blewitt)
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In this episode of the Epigenetics Podcast, we caught up with Akis Papantonis from the University Medical Center Göttingen to talk about his work on genome organisation mediated by RNA Polymerase II.
The research of the Papantonis Laboratory focuses on investigating how environmental signalling stimuli are integrated by chromatin to control homeostatic to deregulated functional transitions. In more detail the equipe is interested in how dynamic higher-order regulatory networks are influenced by the underlying linear DNA fiber. The ultimate goal of the laboratory is to understand general rules governing transcriptional and chromatin homeostasis and finally, how those rules might affect development, ageing or malignancies.
References
- Larkin, J. D., Cook, P. R., & Papantonis, A. (2012). Dynamic reconfiguration of long human genes during one transcription cycle. Molecular and cellular biology, 32(14), 2738–2747. https://doi.org/10.1128/MCB.00179-12
- Diermeier, S., Kolovos, P., Heizinger, L., Schwartz, U., Georgomanolis, T., Zirkel, A., Wedemann, G., Grosveld, F., Knoch, T. A., Merkl, R., Cook, P. R., Längst, G., & Papantonis, A. (2014). TNFα signalling primes chromatin for NF-κB binding and induces rapid and widespread nucleosome repositioning. Genome biology, 15(12), 536. https://doi.org/10.1186/s13059-014-0536-6
- Sofiadis, K., Josipovic, N., Nikolic, M., Kargapolova, Y., Übelmesser, N., Varamogianni-Mamatsi, V., Zirkel, A., Papadionysiou, I., Loughran, G., Keane, J., Michel, A., Gusmao, E. G., Becker, C., Altmüller, J., Georgomanolis, T., Mizi, A., & Papantonis, A. (2021). HMGB1 coordinates SASP-related chromatin folding and RNA homeostasis on the path to senescence. Molecular systems biology, 17(6), e9760. https://doi.org/10.15252/msb.20209760
- Enhancer-promoter contact formation requires RNAPII and antagonizes loop extrusion. Shu Zhang, Nadine Übelmesser, Mariano Barbieri, Argyris Papantonis. bioRxiv 2022.07.04.498738; doi: https://doi.org/10.1101/2022.07.04.498738
Related Episodes
- Chromatin Organization During Development and Disease (Marieke Oudelaar)
- Biophysical Modeling of 3-D Genome Organization (Leonid Mirny)
- Hi-C and Three-Dimensional Genome Sequencing (Erez Lieberman Aiden)
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In this episode of the Epigenetics Podcast, we caught up with Melissa Harrison from the University of Wisconsin-Madison to talk about her work on the “Pioneer” Transcription Factors - Zelda and Grainyhead - and their role at the maternal-to-zygotic transition.
The Harrison lab studies how differentiation and development are driven by coordinated changes in gene expression. To do this, the targets of choice are the transcription factors Zelda and Grainyhead that bind to the genome at specific and crucial points in development and differentiation. These specialised transcription factors have the ability to bind to DNA in the context of nucleosomes which defines regulatory elements and leads to subsequent binding of additional classical transcription factors. These properties allow pioneer factors to act at the top of gene regulatory networks and control developmental transitions.
References
- Harrison, M. M., Botchan, M. R., & Cline, T. W. (2010). Grainyhead and Zelda compete for binding to the promoters of the earliest-expressed Drosophila genes. Developmental biology, 345(2), 248–255. https://doi.org/10.1016/j.ydbio.2010.06.026
- Harrison, M. M., Li, X. Y., Kaplan, T., Botchan, M. R., & Eisen, M. B. (2011). Zelda binding in the early Drosophila melanogaster embryo marks regions subsequently activated at the maternal-to-zygotic transition. PLoS genetics, 7(10), e1002266. https://doi.org/10.1371/journal.pgen.1002266
- McDaniel, S. L., Gibson, T. J., Schulz, K. N., Fernandez Garcia, M., Nevil, M., Jain, S. U., Lewis, P. W., Zaret, K. S., & Harrison, M. M. (2019). Continued Activity of the Pioneer Factor Zelda Is Required to Drive Zygotic Genome Activation. Molecular cell, 74(1), 185–195.e4. https://doi.org/10.1016/j.molcel.2019.01.014
- McDaniel, S. L., & Harrison, M. M. (2019). Optogenetic Inactivation of Transcription Factors in the Early Embryo of Drosophila. Bio-protocol, 9(13), e3296. https://doi.org/10.21769/BioProtoc.3296
- Larson, E.D., Komori, H., Gibson, T.J. et al. Cell-type-specific chromatin occupancy by the pioneer factor Zelda drives key developmental transitions in Drosophila. Nat Commun 12, 7153 (2021). https://doi.org/10.1038/s41467-021-27506-y
Related Episodes
- Pioneer Transcription Factors and Their Influence on Chromatin Structure (Ken Zaret)
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In this episode of the Epigenetics Podcast, we caught up with Elena Gomez-Diaz from the Institute of Parasitology and Biomedicine López-Neyra at the Spanish National Research Council. She share with us her work on the Epigenetics in Human Malaria Parasites.
Elena Gómez-Díaz and her team are focusing on understanding how epigenetic processes are implicated in host-parasite interactions by regulating gene expression in the model of malaria. The team has started to investigate and uncover layers of chromatin regulation that control developmental transitions in Plasmodium falciparum, especially in the parts of the life cycle that take place in the mosquito. Furthermore, the lab has investigated epigenetic changes that are present in malaria-infected Anopheles mosquitos, this led to the identification of cis-regulatory elements and enhancer-promoter networks in response to infection.
References
- Gómez-Díaz E, Rivero A, Chandre F, Corces VG. Insights into the epigenomic landscape of the human malaria vector Anopheles gambiae. Front Genet. 2014 Aug 15;5:277. doi: 10.3389/fgene.2014.00277. PMID: 25177345; PMCID: PMC4133732.
- Gómez-Díaz, E., Yerbanga, R., Lefèvre, T. et al. Epigenetic regulation of Plasmodium falciparum clonally variant gene expression during development in Anopheles gambiae. Sci Rep 7, 40655 (2017). https://doi.org/10.1038/srep40655
- José Luis Ruiz, Juan J Tena, Cristina Bancells, Alfred Cortés, José Luis Gómez-Skarmeta, Elena Gómez-Díaz, Characterization of the accessible genome in the human malaria parasite. Plasmodium falciparum, Nucleic Acids Research, Volume 46, Issue 18, 12 October 2018, Pages 9414–9431, https://doi.org/10.1093/nar/gky643
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Women in Malaria 2021: A Conference Premier. (2021). Trends in Parasitology, 37(7), 573–580. https://doi.org/10.1016/j.pt.2021.04.001
- Twitter Account: https://twitter.com/womeninmalaria
Related Episodes
- Multiple challenges of CUT&Tag (Cassidee McDonough, Kyle Tanguay)
- ATAC-Seq, scATAC-Seq and Chromatin Dynamics in Single-Cells (Jason Buenrostro)
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In this episode of the Epigenetics Podcast, we caught up with Nick Pervolarakis from Active Motif to talk about bioinformatic analysis in epigenetics research.
While many “bench scientists” are familiar with the workflows of ChIP-Seq, ATAC-Seq and CUT&Tag, and even the preparation and analysis of the libraries, the steps between sequencing and fully analyzed data is sometimes thought of as a mystery known only to bioinformatic experts. Most of us have some understanding that the raw data is usually in a file format called a FASTQ. But how do we get from FASTQ files to peaks on a genome browser? This Podcast Episode will provide a peek behind the curtain of the informatic analysis we perform at Active Motif, as part of our end-to-end epigenetic services.
References
- Life in the FASTQ Lane
- Bioinformatics Resource Center
- Epigenetic Services
Related Episodes
- Multiple challenges of ATAC-Seq, Points to Consider (Yuan Xue)
- Multiple challenges of CUT&Tag (Cassidee McDonough, Kyle Tanguay)
- Multiple Challenges in ChIP (Adam Blattler)
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In this episode of the Epigenetics Podcast, we caught up with Ben Delatte Research Scientist at Active Motif to talk about his work on Anchor Based Bisulfite Sequencing.
Whole Genome Bisulfite Sequencing (WGBS) is the current standard for DNA methylation profiling. However, this approach is costly as it requires sequencing coverage over the entire genome. Here we introduce Anchor-Based Bisulfite Sequencing (ABBS). ABBS captures accurate DNA methylation information in Escherichia coli and mammals, while requiring up to 10 times fewer sequencing reads than WGBS. ABBS interrogates the entire genome and is not restricted to the CpG islands assayed by methods like Reduced Representation Bisulfite Sequencing (RRBS). The ABBS protocol is simple and can be performed in a single day.
References
- Chapin, N., Fernandez, J., Poole, J. et al. Anchor-based bisulfite sequencing determines genome-wide DNA methylation. Commun Biol 5, 596 (2022). https://doi.org/10.1038/s42003-022-03543-1
Related Episodes
- The Role of DNA Methylation in Epilepsy (Katja Kobow)
- DNA Methylation and Mammalian Development (Déborah Bourc'his)
- Effects of DNA Methylation on Diabetes (Charlotte Ling)
Contact
- Active Motif on Twitter
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- Email: podcast@activemotif.com
In this episode of the Epigenetics Podcast, we caught up with Ben Delatte Research Scientist at Active Motif to talk about his work on Anchor Based Bisulfite Sequencing.
Whole Genome Bisulfite Sequencing (WGBS) is the current standard for DNA methylation profiling. However, this approach is costly as it requires sequencing coverage over the entire genome. Here we introduce Anchor-Based Bisulfite Sequencing (ABBS). ABBS captures accurate DNA methylation information in Escherichia coli and mammals, while requiring up to 10 times fewer sequencing reads than WGBS. ABBS interrogates the entire genome and is not restricted to the CpG islands assayed by methods like Reduced Representation Bisulfite Sequencing (RRBS). The ABBS protocol is simple and can be performed in a single day.
References
- Chapin, N., Fernandez, J., Poole, J. et al. Anchor-based bisulfite sequencing determines genome-wide DNA methylation. Commun Biol 5, 596 (2022). https://doi.org/10.1038/s42003-022-03543-1
Related Episodes
- The Role of DNA Methylation in Epilepsy (Katja Kobow)
- DNA Methylation and Mammalian Development (Déborah Bourc'his)
- Effects of DNA Methylation on Diabetes (Charlotte Ling)
Contact
- Active Motif on Twitter
- Epigenetics Podcast on Twitter
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- Email: podcast@activemotif.com
In this episode of the Epigenetics Podcast, we caught up with Susanne Mandrup from the University of Southern Denmark to talk about her work on the role of enhancer communities in adipocyte differentiation.
The Laboratory of Susanne Mandrup focuses on the effect of enhancers and enhancer communities on the differentiation of mesenchymal stem cell into adipocytes and osteoblasts. The team has shown that there is significant cross-talk between enhancers and that these form communities of highly interconnected enhancers. Inactive enhancers are then activated by association with these pre-existing enhancer networks to facilitate gene expression in adipocyte differentiation.
References
- Siersbæk R, Rabiee A, Nielsen R, Sidoli S, Traynor S, Loft A, Poulsen LC, Rogowska-Wrzesinska A, Jensen ON, Mandrup S. Transcription factor cooperativity in early adipogenic hotspots and super-enhancers. Cell Rep. 2014 Jun 12;7(5):1443-1455. doi: 10.1016/j.celrep.2014.04.042. Epub 2014 May 22. PMID: 24857652.
- Siersbæk R, Baek S, Rabiee A, Nielsen R, Traynor S, Clark N, Sandelin A, Jensen ON, Sung MH, Hager GL, Mandrup S. Molecular architecture of transcription factor hotspots in early adipogenesis. Cell Rep. 2014 Jun 12;7(5):1434-1442. doi: 10.1016/j.celrep.2014.04.043. Epub 2014 May 22. PMID: 24857666; PMCID: PMC6360525.
- Siersbæk R, Madsen JGS, Javierre BM, Nielsen R, Bagge EK, Cairns J, Wingett SW, Traynor S, Spivakov M, Fraser P, Mandrup S. Dynamic Rewiring of Promoter-Anchored Chromatin Loops during Adipocyte Differentiation. Mol Cell. 2017 May 4;66(3):420-435.e5. doi: 10.1016/j.molcel.2017.04.010. PMID: 28475875.
- Rauch, A., Haakonsson, A.K., Madsen, J.G.S. et al. Osteogenesis depends on commissioning of a network of stem cell transcription factors that act as repressors of adipogenesis. Nat Genet 51, 716–727 (2019). https://doi.org/10.1038/s41588-019-0359-1
- Madsen, J.G.S., Madsen, M.S., Rauch, A. et al. Highly interconnected enhancer communities control lineage-determining genes in human mesenchymal stem cells. Nat Genet 52, 1227–1238 (2020). https://doi.org/10.1038/s41588-020-0709-z
Related Episodes
- Ultraconserved Enhancers and Enhancer Redundancy (Diane Dickel)
- Effects of DNA Methylation on Diabetes (Charlotte Ling)
- Epigenetic Regulation of Stem Cell Self-Renewal and Differentiation (Peggy Goodell)
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In this episode of the Epigenetics Podcast, we caught up with Susanne Mandrup from the University of Southern Denmark to talk about her work on the role of enhancer communities in adipocyte differentiation.
The Laboratory of Susanne Mandrup focuses on the effect of enhancers and enhancer communities on the differentiation of mesenchymal stem cell into adipocytes and osteoblasts. The team has shown that there is significant cross-talk between enhancers and that these form communities of highly interconnected enhancers. Inactive enhancers are then activated by association with these pre-existing enhancer networks to facilitate gene expression in adipocyte differentiation.
References
- Siersbæk R, Rabiee A, Nielsen R, Sidoli S, Traynor S, Loft A, Poulsen LC, Rogowska-Wrzesinska A, Jensen ON, Mandrup S. Transcription factor cooperativity in early adipogenic hotspots and super-enhancers. Cell Rep. 2014 Jun 12;7(5):1443-1455. doi: 10.1016/j.celrep.2014.04.042. Epub 2014 May 22. PMID: 24857652.
- Siersbæk R, Baek S, Rabiee A, Nielsen R, Traynor S, Clark N, Sandelin A, Jensen ON, Sung MH, Hager GL, Mandrup S. Molecular architecture of transcription factor hotspots in early adipogenesis. Cell Rep. 2014 Jun 12;7(5):1434-1442. doi: 10.1016/j.celrep.2014.04.043. Epub 2014 May 22. PMID: 24857666; PMCID: PMC6360525.
- Siersbæk R, Madsen JGS, Javierre BM, Nielsen R, Bagge EK, Cairns J, Wingett SW, Traynor S, Spivakov M, Fraser P, Mandrup S. Dynamic Rewiring of Promoter-Anchored Chromatin Loops during Adipocyte Differentiation. Mol Cell. 2017 May 4;66(3):420-435.e5. doi: 10.1016/j.molcel.2017.04.010. PMID: 28475875.
- Rauch, A., Haakonsson, A.K., Madsen, J.G.S. et al. Osteogenesis depends on commissioning of a network of stem cell transcription factors that act as repressors of adipogenesis. Nat Genet 51, 716–727 (2019). https://doi.org/10.1038/s41588-019-0359-1
- Madsen, J.G.S., Madsen, M.S., Rauch, A. et al. Highly interconnected enhancer communities control lineage-determining genes in human mesenchymal stem cells. Nat Genet 52, 1227–1238 (2020). https://doi.org/10.1038/s41588-020-0709-z
Related Episodes
- Ultraconserved Enhancers and Enhancer Redundancy (Diane Dickel)
- Effects of DNA Methylation on Diabetes (Charlotte Ling)
- Epigenetic Regulation of Stem Cell Self-Renewal and Differentiation (Peggy Goodell)
Contact
- Active Motif on Twitter
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In this episode of the Epigenetics Podcast, we caught up with Marco Trizzino from Thomas Jefferson University to talk about his work on transposable elements in gene regulation and evolution.
Marco Trizzino and his team focus on characterising transposable elements and how they affect gene regulation, evolution and ageing in primates. They could show that transposable elements that integrated into the genome turned into regulatory elements in the genome, like enhancers. They then contribute to regulation of processes like development or ageing, which could be among those factors that lead to increased brain development or longevity in great apes.
References
- Trizzino M, Park Y, Holsbach-Beltrame M, Aracena K, Mika K, Caliskan M, Perry GH, Lynch VJ, Brown CD. Transposable elements are the primary source of novelty in primate gene regulation. Genome Res. 2017 Oct;27(10):1623-1633. doi: 10.1101/gr.218149.116. Epub 2017 Aug 30. PMID: 28855262; PMCID: PMC5630026.
- Pagliaroli L, Porazzi P, Curtis AT, Scopa C, Mikkers HMM, Freund C, Daxinger L, Deliard S, Welsh SA, Offley S, Ott CA, Calabretta B, Brugmann SA, Santen GWE, Trizzino M. Inability to switch from ARID1A-BAF to ARID1B-BAF impairs exit from pluripotency and commitment towards neural crest formation in ARID1B-related neurodevelopmental disorders. Nat Commun. 2021 Nov 9;12(1):6469. doi: 10.1038/s41467-021-26810-x. PMID: 34753942; PMCID: PMC8578637.
- Tejada-Martinez D, Avelar RA, Lopes I, Zhang B, Novoa G, de Magalhães JP, Trizzino M. Positive Selection and Enhancer Evolution Shaped Lifespan and Body Mass in Great Apes. Mol Biol Evol. 2022 Feb 3;39(2):msab369. doi: 10.1093/molbev/msab369. PMID: 34971383; PMCID: PMC8837823.
- Young transposable elements rewired gene regulatory networks in human and chimpanzee hippocampal intermediate progenitors. Sruti Patoori, Samantha M. Barnada, Christopher Large, John I. Murray, Marco Trizzino. bioRxiv 2021.11.24.469877; doi: https://doi.org/10.1101/2021.11.24.469877
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In this episode of the Epigenetics Podcast, we caught up with Marcela Sjöberg from the Pontificia Universidad Católica de Chile to talk about her work on the hydroxymethylation landscape in immune cells.
At the beginning of her career Marcela Sjöberg worked on Aurora B and Polycomb and how modifications placed by them modulate the binding of RNA Pol II. Later, her focus shifted to examine cytosine DNA methylation and hydroxymethylation changes in immune cells and how the epigenetic state of these marks varies between individuals and is reprogrammed for Metastable Epialleles in mouse. More recently, the laboratory is interested on how hydroxymethylation of transcription factor binding motifs influence binding and activity of the respective transcription factors in immune cells.
References
- Sabbattini, P., Sjoberg, M., Nikic, S., Frangini, A., Holmqvist, P.-H., Kunowska, N., Carroll, T., Brookes, E., Arthur, S. J., Pombo, A., & Dillon, N. (2014). An H3K9/S10 methyl-phospho switch modulates Polycomb and Pol II binding at repressed genes during differentiation. Molecular Biology of the Cell, 25(6), 904–915. https://doi.org/10.1091/mbc.e13-10-0628
- Kazachenka, A., Bertozzi, T. M., Sjoberg-Herrera, M. K., Walker, N., Gardner, J., Gunning, R., Pahita, E., Adams, S., Adams, D., & Ferguson-Smith, A. C. (2018). Identification, Characterization, and Heritability of Murine Metastable Epialleles: Implications for Non-genetic Inheritance. Cell, 175(5), 1259-1271.e13. https://doi.org/10.1016/j.cell.2018.09.043
- Westoby, J., Herrera, M.S., Ferguson-Smith, A.C. et al. Simulation-based benchmarking of isoform quantification in single-cell RNA-seq. Genome Biol 19, 191 (2018). https://doi.org/10.1186/s13059-018-1571-5
- Viner, C., Johnson, J., Walker, N., Shi, H., Sjöberg, M., Adams, D. J., Ferguson-Smith, A. C., Bailey, T. L., & Hoffman, M. M. (2016). Modeling methyl-sensitive transcription factor motifs with an expanded epigenetic alphabet [Preprint]. Bioinformatics. https://doi.org/10.1101/043794
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In this episode of the Epigenetics Podcast, we caught up with Tim Petros from the Eunice Kennedy Shriver National Institute of Child Health and Human Development at the NIH to talk about his work on Single Cell Epigenomics in Neuronal Development.
The Petros lab focuses on “interneurons”, their diversity and how environmental signals interact to generate this diversity. This subgroup of neurons comprise about 20% of neutrons in the brain, however, they are the primary source of inhibition. Furthermore, interneurons are critical components in modulating information flow throughout the nervous system. The Petros lab seeks to uncover the genetic programs that lead to the incredible diversity in interneurons, as well as how the local environment influences this process.
To lay a foundation for this and to provide a data-base for other researchers the Petros lab generated an epigenome atlas of neural progenitor cells of the mouse brain. This data includes scRNA-Seq, snATAC-Seq, CUT&Tag (H3K4me3, H3K27me3), CUT&RUN (H3K27ac), Hi-C and Capture-C. This data can be downloaded at the link below:
https://www.nichd.nih.gov/research/atNICHD/Investigators/petros/data-sharing
References
- Datasets: https://www.nichd.nih.gov/research/atNICHD/Investigators/petros/data-sharing
- Quattrocolo G, Fishell G, Petros TJ. Heterotopic Transplantations Reveal Environmental Influences on Interneuron Diversity and Maturation. Cell Rep. 2017 Oct 17;21(3):721-731. doi: 10.1016/j.celrep.2017.09.075. PMID: 29045839; PMCID: PMC5662128.
- Dongjin R Lee, Christopher Rhodes, Apratim Mitra, Yajun Zhang, Dragan Maric, Ryan K Dale, Timothy J Petros (2022) Transcriptional heterogeneity of ventricular zone cells in the ganglionic eminences of the mouse forebrain eLife 11:e71864 https://doi.org/10.7554/eLife.71864
- Rhodes, C. T., Thompson, J. J., Mitra, A., Asokumar, D., Lee, D. R., Lee, D. J., Zhang, Y., Jason, E., Dale, R. K., Rocha, P. P., & Petros, T. J. (2022). An epigenome atlas of neural progenitors within the embryonic mouse forebrain. Nature communications, 13(1), 4196. https://doi.org/10.1038/s41467-022-31793-4
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In this episode of the Epigenetics Podcast, we caught up with Nada Jabado from McGill University to talk about her work on oncohistones as drivers of Pediatric Brain Tumors.
Nada Jabado and her team were amongst the first to identify mutations in Histone 3.3 Tails which lead to differentially remodeled chromatin in pediatric glioblastoma. Mutations that occur include the Lysine at position 27 and the Glycine at position 34. If those residues are mutated it will influence the equilibrium of chromatin associated proteins like the Polycomb Repressive Complex (PRC) and hence domains of heterochromatin will be shifted. This, in turn, will lead to differential gene expression and development of developmental disorders or cancer.
References
- Schwartzentruber, J., Korshunov, A., Liu, X. Y., Jones, D. T., Pfaff, E., Jacob, K., Sturm, D., Fontebasso, A. M., Quang, D. A., Tönjes, M., Hovestadt, V., Albrecht, S., Kool, M., Nantel, A., Konermann, C., Lindroth, A., Jäger, N., Rausch, T., Ryzhova, M., Korbel, J. O., … Jabado, N. (2012). Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma. Nature, 482(7384), 226–231. https://doi.org/10.1038/nature10833
- Kleinman, C. L., Gerges, N., Papillon-Cavanagh, S., Sin-Chan, P., Pramatarova, A., Quang, D. A., Adoue, V., Busche, S., Caron, M., Djambazian, H., Bemmo, A., Fontebasso, A. M., Spence, T., Schwartzentruber, J., Albrecht, S., Hauser, P., Garami, M., Klekner, A., Bognar, L., Montes, J. L., … Jabado, N. (2014). Fusion of TTYH1 with the C19MC microRNA cluster drives expression of a brain-specific DNMT3B isoform in the embryonal brain tumor ETMR. Nature genetics, 46(1), 39–44. https://doi.org/10.1038/ng.2849
- Papillon-Cavanagh, S., Lu, C., Gayden, T., Mikael, L. G., Bechet, D., Karamboulas, C., Ailles, L., Karamchandani, J., Marchione, D. M., Garcia, B. A., Weinreb, I., Goldstein, D., Lewis, P. W., Dancu, O. M., Dhaliwal, S., Stecho, W., Howlett, C. J., Mymryk, J. S., Barrett, J. W., Nichols, A. C., … Jabado, N. (2017). Impaired H3K36 methylation defines a subset of head and neck squamous cell carcinomas. Nature genetics, 49(2), 180–185. https://doi.org/10.1038/ng.3757
- Chen, C., Deshmukh, S., Jessa, S., Hadjadj, D., Lisi, V., Andrade, A. F., Faury, D., Jawhar, W., Dali, R., Suzuki, H., Pathania, M., A, D., Dubois, F., Woodward, E., Hébert, S., Coutelier, M., Karamchandani, J., Albrecht, S., Brandner, S., De Jay, N., … Jabado, N. (2020). Histone H3.3G34-Mutant Interneuron Progenitors Co-opt PDGFRA for Gliomagenesis. Cell, 183(6), 1617–1633.e22. https://doi.org/10.1016/j.cell.2020.11.012
- Chaouch, A., Berlandi, J., Chen, C., Frey, F., Badini, S., Harutyunyan, A. S., Chen, X., Krug, B., Hébert, S., Jeibmann, A., Lu, C., Kleinman, C. L., Hasselblatt, M., Lasko, P., Shirinian, M., & Jabado, N. (2021). Histone H3.3 K27M and K36M mutations de-repress transposable elements through perturbation of antagonistic chromatin marks. Molecular cell, 81(23), 4876–4890.e7. https://doi.org/10.1016/j.molcel.2021.10.008
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In this episode of the Epigenetics Podcast, we caught up with Goncalo Castelo-Branco from the Karolinska Institute to talk about his work on the characterization of epigenetic states in the Oligodendrocyte Lineage.
The group from Gonçalo Castelo-Branco’s lab focuses on characterizing epigenetic states of oligodendrocytes, with the aim to understand their contribution to diseases like multiple sclerosis. To do this the group used single-cell RNA-Seq to identify sub-populations of oligodendrocytes. Furthermore, the team pioneered improvements in CUT&Tag and applied it to the single-cell space, as well as developing spatial CUT&Tag. More recently they used nanobodies in an optimised version of single cell CUT&Tag that allows simultaneous probing of three epigenomic modalities at single-cell resolution, using nanobody-Tn5 fusion proteins. The three modalities encompass chromatin accessibility as measured via ATAC-Seq and two histone post-transcriptional modifications.
References
- Deng Y, Bartosovic M, Kukanja P, Zhang D, Liu Y, Su G, Enninful A, Bai Z, Castelo-Branco G, Fan R. Spatial-CUT&Tag: Spatially resolved chromatin modification profiling at the cellular level. Science. 2022 Feb 11;375(6581):681-686. doi: 10.1126/science.abg7216. Epub 2022 Feb 10. PMID: 35143307.
- Winick-Ng W, Kukalev A, Harabula I, Zea-Redondo L, Szabó D, Meijer M, Serebreni L, Zhang Y, Bianco S, Chiariello AM, Irastorza-Azcarate I, Thieme CJ, Sparks TM, Carvalho S, Fiorillo L, Musella F, Irani E, Torlai Triglia E, Kolodziejczyk AA, Abentung A, Apostolova G, Paul EJ, Franke V, Kempfer R, Akalin A, Teichmann SA, Dechant G, Ungless MA, Nicodemi M, Welch L, Castelo-Branco G, Pombo A. Cell-type specialization is encoded by specific chromatin topologies. Nature. 2021 Nov;599(7886):684-691. doi: 10.1038/s41586-021-04081-2. Epub 2021 Nov 17. PMID: 34789882; PMCID: PMC8612935.
- Bartosovic M, Kabbe M, Castelo-Branco G. Single-cell CUT&Tag profiles histone modifications and transcription factors in complex tissues. Nat Biotechnol. 2021 Jul;39(7):825-835. doi: 10.1038/s41587-021-00869-9. Epub 2021 Apr 12. PMID: 33846645; PMCID: PMC7611252.
- Marek Bartosovic, Gonçalo Castelo-Branco. Multimodal chromatin profiling using nanobody-based single-cell CUT&Tag. bioRxiv. 2022.03.08.483459; doi: https://doi.org/10.1101/2022.03.08.483459
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In this episode of the Epigenetics Podcast, we caught up with Active Motif’s own Yuan Xue to talk about some of the challenges of performing ATAC-Seq.
ATAC-Seq stands for Assay for Transposase-Accessible Chromatin with high-throughput sequencing and was initially described by Jason Buenrostro in 2013. The ATAC-Seq method relies on next-generation sequencing (NGS) library construction using the hyperactive transposase Tn5. NGS adapters are loaded onto the transposase, which allows simultaneous fragmentation of chromatin and integration of those adapters into open chromatin regions. ATAC-Seq is an attractive method to start your epigenetic journey. Whether you want to analyze the state of the chromatin in your sample or compare the chromatin state before and after a special treatment, ATAC-Seq allows you to investigate genome-wide chromatin changes and can offer guidelines about which epigenetic modification or transcription factor should be studied next in the follow-up experiments and which method should be used to study them.
In this Episode we go through the Protocol in detail and discuss potential challenges and points to pay attention to when starting your first ATAC-Seq experiment.
References
- ATAC-Seq Resource Center
- Complete Guide to Understanding and Using ATAC-Seq
- Beginner’s Guide to Understanding Single-Cell ATAC-Seq
- Buenrostro, J. D., Giresi, P. G., Zaba, L. C., Chang, H. Y., & Greenleaf, W. J. (2013). Transposition of native chromatin for fast and sensitive epigenomic profiling of open chromatin, DNA-binding proteins and nucleosome position. Nature methods, 10(12), 1213–1218. https://doi.org/10.1038/nmeth.2688
- Buenrostro, J. D., Wu, B., Litzenburger, U. M., Ruff, D., Gonzales, M. L., Snyder, M. P., Chang, H. Y., & Greenleaf, W. J. (2015). Single-cell chromatin accessibility reveals principles of regulatory variation. Nature, 523(7561), 486–490. https://doi.org/10.1038/nature14590
- Cusanovich, D. A., Daza, R., Adey, A., Pliner, H. A., Christiansen, L., Gunderson, K. L., Steemers, F. J., Trapnell, C., & Shendure, J. (2015). Multiplex single cell profiling of chromatin accessibility by combinatorial cellular indexing. Science (New York, N.Y.), 348(6237), 910–914. https://doi.org/10.1126/science.aab1601
- Podcast: ATAC-Seq, scATAC-Seq and Chromatin Dynamics in Single-Cells (Jason Buenrostro)
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In this episode of the Epigenetics Podcast, we caught up with John Rinn from the University of Colorado in Boulder to talk about his work on the role of lncRNAs in gene expression and nuclear organization.
The Rinn Lab pioneered the approach of screening the human genome for long noncoding RNAs (lncRNAs). More recently, the lab has shifted focus from measuring the number of lncRNAs to finding lncRNAs that have a distinct biological function in human health and disease. One example of such a lncRNA is FIRRE, which is present in all animals, however the sequence is not conserved, except for in primates. FIRRE contains many interesting features, such as repeat sequences and CTCF binding sites. In absence of FIRRE, defects in the immune system can be observed and also some brain defects may also be observed.
References
- Carter, T., Singh, M., Dumbovic, G., Chobirko, J. D., Rinn, J. L., & Feschotte, C. (2022). Mosaic cis-regulatory evolution drives transcriptional partitioning of HERVH endogenous retrovirus in the human embryo. eLife, 11, e76257. Advance online publication. https://doi.org/10.7554/eLife.76257
- Long, Y., Hwang, T., Gooding, A. R., Goodrich, K. J., Rinn, J. L., & Cech, T. R. (2020). RNA is essential for PRC2 chromatin occupancy and function in human pluripotent stem cells. Nature Genetics, 52(9), 931–938. https://doi.org/10.1038/s41588-020-0662-x
- Kelley, D., & Rinn, J. (2012). Transposable elements reveal a stem cell-specific class of long noncoding RNAs. Genome biology, 13(11), R107. https://doi.org/10.1186/gb-2012-13-11-r107
- Khalil, A. M., Guttman, M., Huarte, M., Garber, M., Raj, A., Rivea Morales, D., Thomas, K., Presser, A., Bernstein, B. E., van Oudenaarden, A., Regev, A., Lander, E. S., & Rinn, J. L. (2009). Many human large intergenic noncoding RNAs associate with chromatin-modifying complexes and affect gene expression. Proceedings of the National Academy of Sciences, 106(28), 11667–11672. https://doi.org/10.1073/pnas.0904715106
- Guttman, M., Amit, I., Garber, M., French, C., Lin, M. F., Feldser, D., Huarte, M., Zuk, O., Carey, B. W., Cassady, J. P., Cabili, M. N., Jaenisch, R., Mikkelsen, T. S., Jacks, T., Hacohen, N., Bernstein, B. E., Kellis, M., Regev, A., Rinn, J. L., & Lander, E. S. (2009). Chromatin signature reveals over a thousand highly conserved large non-coding RNAs in mammals. Nature, 458(7235), 223–227. https://doi.org/10.1038/nature07672
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In this episode of the Epigenetics Podcast, we caught up with Morgan Levine from Altos lab to talk about her work on Epigenetic Clocks and Biomarkers of Ageing.
The Levine Lab focuses on deciphering mechanisms that lead to epigenetic ageing, which can be measured by epigenetic clocks. Epigenetic clocks were first described in 2011 by Bocklandt et al.. Later-on, the Horvath and the Hannum clock were described by using a combination of CpGs to calculate biological/epigenetic age in contrast to chronological age.
The Levine Lab themselves worked on generating an advanced version of an Epigenetic clock, called "DNAm PhenoAge" that will now be used, and not only in human samples. The team now moves to mouse models and to cells in a dish and using those models to investigate the mechanisms behind epigenetic aging.
References
- Liu, Z., Leung, D., Thrush, K., Zhao, W., Ratliff, S., Tanaka, T., Schmitz, L. L., Smith, J. A., Ferrucci, L., & Levine, M. E. (2020). Underlying features of epigenetic aging clocks in vivo and in vitro. Aging cell, 19(10), e13229. https://doi.org/10.1111/acel.13229
- Levine, M. E., Lu, A. T., Quach, A., Chen, B. H., Assimes, T. L., Bandinelli, S., Hou, L., Baccarelli, A. A., Stewart, J. D., Li, Y., Whitsel, E. A., Wilson, J. G., Reiner, A. P., Aviv, A., Lohman, K., Liu, Y., Ferrucci, L., & Horvath, S. (2018). An epigenetic biomarker of aging for lifespan and healthspan. Aging, 10(4), 573–591. https://doi.org/10.18632/aging.101414
- Levine, M., McDevitt, R. A., Meer, M., Perdue, K., Di Francesco, A., Meade, T., Farrell, C., Thrush, K., Wang, M., Dunn, C., Pellegrini, M., de Cabo, R., & Ferrucci, L. (2020). A rat epigenetic clock recapitulates phenotypic aging and co-localizes with heterochromatin. eLife, 9, e59201. https://doi.org/10.7554/eLife.59201
- Kuo, C. L., Pilling, L. C., Atkins, J. C., Masoli, J., Delgado, J., Tignanelli, C., Kuchel, G., Melzer, D., Beckman, K. B., & Levine, M. (2020). COVID-19 severity is predicted by earlier evidence of accelerated aging. medRxiv : the preprint server for health sciences, 2020.07.10.20147777. https://doi.org/10.1101/2020.07.10.20147777
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In this episode of the Epigenetics Podcast, we caught up with Jan Żylicz from the Novo Nordisk Foundation Center for Stem Cell Medicine to talk about his work on epigenetic and metabolic regulation of early development.
The focus of the Żylicz Lab is studying early development and how this process is influenced by epigenetic factors. In more detail, the Team focuses on the function of chromatin modifiers in this process. Primed pluripotent epiblasts in vivo show a distinct chromatin landscape that is characterized by high levels of histone H3 lysine 9 dimethylation (H3K9me2) and rearranged Polycomb-associated histone H3 lysine 27 trimethylation (H3K27me3) at thousands of genes along the genome. However, the function of only about 100 loci is impaired. The Żylicz Lab tries to understand this process behind and also the cause of this discrepancy.
References
- Żylicz, J. J., Bousard, A., Žumer, K., Dossin, F., Mohammad, E., da Rocha, S. T., Schwalb, B., Syx, L., Dingli, F., Loew, D., Cramer, P., & Heard, E. (2019). The Implication of Early Chromatin Changes in X Chromosome Inactivation. Cell, 176(1–2), 182-197.e23. https://doi.org/10.1016/j.cell.2018.11.041
- Dossin, F., Pinheiro, I., Żylicz, J. J., Roensch, J., Collombet, S., Le Saux, A., Chelmicki, T., Attia, M., Kapoor, V., Zhan, Y., Dingli, F., Loew, D., Mercher, T., Dekker, J., & Heard, E. (2020). SPEN integrates transcriptional and epigenetic control of X-inactivation. Nature, 578(7795), 455–460. https://doi.org/10.1038/s41586-020-1974-9
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In this episode of the Epigenetics Podcast, we caught up with Active Motif scientists Casidee McDonough from Epigenetic Services and Kyle Tanguay from R&D to talk about technical details of the CUT&Tag protocol and current developments around this method in our R&D Team.
CUT&Tag, which is short for Cleavage Under Targets and Tagmentation, is a molecular biology method that is used to investigate interactions between proteins and DNA and to identify DNA binding sites for their protein of interest. Although CUT&Tag is similar in some ways to ChIP assays, the starting material for CUT&Tag is live, permeabilized cells or isolated cell nuclei, rather than cells or tissue that have been crosslinked with formaldehyde as is the case when performing ChIP. The CUT&Tag method is very sensitive and has been reported to work with as few as 60 cells for some histone modifications. The ability to work with such small numbers of cells is an advantage for researchers working on specific cell types, such as rare neuronal populations, pancreatic islets, or stem cells that are difficult to obtain in large numbers.
In this Episode we discuss the CUT&Tag workflow in detail, talk about the challenges and pitfalls, give guidelines on how to do a good CUT&Tag experiment and offer a glimpse into the future of CUT&Tag product development at Active Motif.
References
- Comprehensive Guide to Understanding and Using CUT&Tag Assays
- Library QC for ATAC-Seq and CUT&Tag | AKA “Does My Library Look Okay?”
- Kaya-Okur, H.S., Wu, S.J., Codomo, C.A. et al. CUT&Tag for efficient epigenomic profiling of small samples and single cells. Nat Commun 10, 1930 (2019). https://doi.org/10.1038/s41467-019-09982-5
- Podcast: Chromatin Profiling: From ChIP to CUT&RUN, CUT&Tag and CUTAC (Steven Henikoff)
- CUT&Tag-validated antibodies
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In this episode of the Epigenetics Podcast, we caught up with Ian Maze from Ichan School of Medicine at Mount Sinai and a Howard Hughes Medical Institute (HHMI) Investigator to talk about his work on the role of histone dopaminylation and serotinylation in neuronal plasticity.
The Maze group focuses on understanding the complex interplay between chromatin regulatory mechanisms in brain and neuronal plasticity. The lab places an emphasis on psychiatric disorders associated with monoaminergic (e.g., serotonin, dopamine, etc.) dysfunction, such as major depressive disorder and drug addiction. In particular the Maze team has investigated cocaine addiction and its effect on chromatin by serotonylation and dopaminylation of Histone H3 Tails.
References
- Maze, I., Covington, H. E., Dietz, D. M., LaPlant, Q., Renthal, W., Russo, S. J., Mechanic, M., Mouzon, E., Neve, R. L., Haggarty, S. J., Ren, Y., Sampath, S. C., Hurd, Y. L., Greengard, P., Tarakhovsky, A., Schaefer, A., & Nestler, E. J. (2010). Essential Role of the Histone Methyltransferase G9a in Cocaine-Induced Plasticity. Science, 327(5962), 213–216. https://doi.org/10.1126/science.1179438
- Farrelly, L. A., Thompson, R. E., Zhao, S., Lepack, A. E., Lyu, Y., Bhanu, N. V., Zhang, B., Loh, Y.-H. E., Ramakrishnan, A., Vadodaria, K. C., Heard, K. J., Erikson, G., Nakadai, T., Bastle, R. M., Lukasak, B. J., Zebroski, H., Alenina, N., Bader, M., Berton, O., … Maze, I. (2019). Histone serotonylation is a permissive modification that enhances TFIID binding to H3K4me3. Nature, 567(7749), 535–539. https://doi.org/10.1038/s41586-019-1024-7
- Lepack, A. E., Werner, C. T., Stewart, A. F., Fulton, S. L., Zhong, P., Farrelly, L. A., Smith, A. C. W., Ramakrishnan, A., Lyu, Y., Bastle, R. M., Martin, J. A., Mitra, S., O’Connor, R. M., Wang, Z.-J., Molina, H., Turecki, G., Shen, L., Yan, Z., Calipari, E. S., … Maze, I. (2020). Dopaminylation of histone H3 in ventral tegmental area regulates cocaine seeking. Science, 368(6487), 197–201. https://doi.org/10.1126/science.aaw8806
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In this episode of the Epigenetics Podcast, we caught up with Erna Magnúsdóttir from the University of Iceland to talk about her work on the role of Blimp-1 in immune-cell differentiation.
The Magnúsdóttir Lab is interested in how the mammalian genome is interpreted in a context dependent manner, leading to different cellular states, by using mouse primordial germ cells as well as mouse and human B-cells as model systems. More specifically, the team is interested in the Transcription Factor Blimp-1 and its effect on immune cell differentiation. Next to its function in immune cells, Blimp-1 also plays a role in Waldenström’s macroglobulinemia. The lab hopes to reveal the intricacies in disease progression and alteration in cellular states to increasingly aggressive tumor behavior.
References
- Magnúsdóttir, E., Dietmann, S., Murakami, K. et al. A tripartite transcription factor network regulates primordial germ cell specification in mice. Nat Cell Biol 15, 905–915 (2013). https://doi.org/10.1038/ncb2798
- Anderson, K.J., Ósvaldsdóttir, Á.B., Atzinger, B. et al. The BLIMP1—EZH2 nexus in a non-Hodgkin lymphoma. Oncogene 39, 5138–5151 (2020). https://doi.org/10.1038/s41388-020-1347-8
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In this episode of the Epigenetics Podcast, we speak with Peter Smibert, Vice President of Biology at 10X Genomics to talk about an exciting new method in Multimodal Characterization of Cellular Identity using Barcoding.
During his time at the New York Genome Center, Peter Smibert was instrumental in the development of a new method called "Cellular Indexing of Transcriptomes and Epitopes by Sequencing" short CITE-Seq. This method enables the characterization of a cell's transcriptome, while at the same time, also allows the characterization of the cell's protein surface markers - at the single cell level. In CITE-Seq, sequencing adapters are coupled to antibodies that recognize surface proteins, which can then be detected by sequencing.
Further advancements of the CITE-Seq method led to the launch of BioLegend’s TOTAL-Seq and the integration of scATAC-Seq into the workflow. With the integration of scATAC-Seq in the CITE-Seq protocol, it is now possible to characterize single-cells along the path of the central dogma of biology, this is why the method called DOGMA-Seq.
References
- https://cite-seq.com
- Baron, M., Yanai, I. New skin for the old RNA-Seq ceremony: the age of single-cell multi-omics. Genome Biol 18, 159 (2017). https://doi.org/10.1186/s13059-017-1300-5
- Stoeckius, M., Zheng, S., Houck-Loomis, B. et al. Cell Hashing with barcoded antibodies enables multiplexing and doublet detection for single cell genomics. Genome Biol 19, 224 (2018). https://doi.org/10.1186/s13059-018-1603-1
- Stoeckius, M., Hafemeister, C., Stephenson, W. et al. Simultaneous epitope and transcriptome measurement in single cells. Nat Methods 14, 865–868 (2017). https://doi.org/10.1038/nmeth.4380
- Mimitou, E.P., Cheng, A., Montalbano, A. et al. Multiplexed detection of proteins, transcriptomes, clonotypes and CRISPR perturbations in single cells. Nat Methods 16, 409–412 (2019). https://doi.org/10.1038/s41592-019-0392-0
Related Episodes
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- ATAC-Seq, scATAC-Seq and Chromatin Dynamics in Single-Cells
- Investigating the Dynamics of Epigenetic Plasticity in Cancer with Single Cell Technologies (Céline Vallot)
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In this episode of the Epigenetics Podcast, we caught up with Sara Wickström, Director at the Max Planck Institute for Molecular Biomedicine in Münster, to talk about her work on the effect of mechanotransduction on chromatin structure and transcription in stem cells.
Sara Wickström and her team focus on the stem cell niche and how that niche affects stem cell function. In order to study the native niche and to even be able to manipulate it, the Wickström Lab was able to develop a ex vivo culture system, allowing systematic identification of factors driving stem cell dynamics and plasticity.
Stem cells in the stem cell niche are exposed to external stimuli such as physical forces which control their growth, fate and self renewal. Recent work in the Wickström lab showed how mechanical signals influence transcriptional regulation, chromatin organization, and nuclear architecture and how this affects aging or lineage commitment. In this Episode we also discuss how chromatin can act as a sensor of mechanical signals taking advantage of the different physical properties of eu- and heterochromatin.
References
- Le, H. Q., Ghatak, S., Yeung, C. Y., Tellkamp, F., Günschmann, C., Dieterich, C., Yeroslaviz, A., Habermann, B., Pombo, A., Niessen, C. M., & Wickström, S. A. (2016). Mechanical regulation of transcription controls Polycomb-mediated gene silencing during lineage commitment. Nature cell biology, 18(8), 864–875. https://doi.org/10.1038/ncb3387
- Nava, M. M., Miroshnikova, Y. A., Biggs, L. C., Whitefield, D. B., Metge, F., Boucas, J., Vihinen, H., Jokitalo, E., Li, X., García Arcos, J. M., Hoffmann, B., Merkel, R., Niessen, C. M., Dahl, K. N., & Wickström, S. A. (2020). Heterochromatin-Driven Nuclear Softening Protects the Genome against Mechanical Stress-Induced Damage. Cell, 181(4), 800–817.e22. https://doi.org/10.1016/j.cell.2020.03.052
- Koester, J., Miroshnikova, Y. A., Ghatak, S., Chacón-Martínez, C. A., Morgner, J., Li, X., Atanassov, I., Altmüller, J., Birk, D. E., Koch, M., Bloch, W., Bartusel, M., Niessen, C. M., Rada-Iglesias, A., & Wickström, S. A. (2021). Niche stiffening compromises hair follicle stem cell potential during ageing by reducing bivalent promoter accessibility. Nature cell biology, 23(7), 771–781. https://doi.org/10.1038/s41556-021-00705-x
- Maki, K., Nava, M. M., Villeneuve, C., Chang, M., Furukawa, K. S., Ushida, T., & Wickström, S. A. (2021). Hydrostatic pressure prevents chondrocyte differentiation through heterochromatin remodeling. Journal of cell science, 134(2), jcs247643. https://doi.org/10.1242/jcs.247643
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In this episode of the Epigenetics Podcast, we caught up with Ben Hindson, Chief Scientific Officer at 10X Genomics, to talk about single-cell technologies using microfluidics.
Epigenetics has moved well past a simple understanding of a single epigenetic layer of control at genomic regions of interest, thanks to advances in many techniques and the application of “multiomics”. We can now analyze genome-wide histone modification patterns, transcription factor binding profiles, chromatin accessibility profiles, three-dimensional chromosomal conformation, and DNA methylation dynamics combined with transcriptomic analyses and associated analytical platforms.
Bulk Assays, like ATAC-Seq or ChIP, despite all their advantages, do not provide information about the chromatin states of individual subpopulations of cells within a sample. To identify chromatin features in heterogeneous populations, such as blood, pancreas, and brain, those analysis need to be performed at a single-cell level. 10X Genomics has been at the forefront of the movement into the single cell space and in this Episode we discuss this work with Ben Hindson, CSO of 10X genomics.
References
- https://www.10xgenomics.com/products/single-cell-multiome-atac-plus-gene-expression
- Spectrum of Innovation
- Multiomic Epigenetic Analysis Turns Short Stories into Epic Tales
- Single-Cell Multiome Service
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In this episode of the Epigenetics Podcast, we caught up with Eleni Tomazou from St. Anna Children's Cancer Research Institute in Vienna to talk about her work on Epigenome-based precision medicine.
The Tomazou lab studies Ewing sarcoma and the effects of Epigenetic factors on this disease. Ewing sarcoma is a type of cancer that affects bone and soft tissue of children and young adults, with a peak incidence at the age of 15. Ewing sarcoma is among the pediatric cancer types with the lowest survival rates and the development of novel therapies was obstructed by the limited understanding of the mechanisms behind the disease.
Work done in Eleni Tomazou's group identified an epigenetic signature of Ewing sarcoma which, ultimately, lead to the possibility to diagnose Ewing sarcoma from liquid biopsies. The team is now looking to find actionable targets like enhancers to develop therapies, finding biomarkers to enable disease monitoring, and to further characterize these tumors to decipher intra-tumor epigenetic heterogeneity and characterize the developmental stage of the cell of origin.
References
- Tomazou, E. M., Sheffield, N. C., Schmidl, C., Schuster, M., Schönegger, A., Datlinger, P., Kubicek, S., Bock, C., & Kovar, H. (2015). Epigenome Mapping Reveals Distinct Modes of Gene Regulation and Widespread Enhancer Reprogramming by the Oncogenic Fusion Protein EWS-FLI1. Cell Reports, 10(7), 1082–1095. https://doi.org/10.1016/j.celrep.2015.01.042
- Sheffield, N. C., Pierron, G., Klughammer, J., Datlinger, P., Schönegger, A., Schuster, M., Hadler, J., Surdez, D., Guillemot, D., Lapouble, E., Freneaux, P., Champigneulle, J., Bouvier, R., Walder, D., Ambros, I. M., Hutter, C., Sorz, E., Amaral, A. T., de Álava, E., … Tomazou, E. M. (2017). DNA methylation heterogeneity defines a disease spectrum in Ewing sarcoma. Nature Medicine, 23(3), 386–395. https://doi.org/10.1038/nm.4273
- Terlecki-Zaniewicz, S., Humer, T., Eder, T., Schmoellerl, J., Heyes, E., Manhart, G., Kuchynka, N., Parapatics, K., Liberante, F. G., Müller, A. C., Tomazou, E. M., & Grebien, F. (2021). Biomolecular condensation of NUP98 fusion proteins drives leukemogenic gene expression. Nature Structural & Molecular Biology, 28(2), 190–201. https://doi.org/10.1038/s41594-020-00550-w
- Peneder, P., Stütz, A. M., Surdez, D., Krumbholz, M., Semper, S., Chicard, M., Sheffield, N. C., Pierron, G., Lapouble, E., Tötzl, M., Ergüner, B., Barreca, D., Rendeiro, A. F., Agaimy, A., Boztug, H., Engstler, G., Dworzak, M., Bernkopf, M., Taschner-Mandl, S., … Tomazou, E. M. (2021). Multimodal analysis of cell-free DNA whole-genome sequencing for pediatric cancers with low mutational burden. Nature Communications, 12(1), 3230. https://doi.org/10.1038/s41467-021-23445-w
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In this episode of the Epigenetics Podcast, we caught up with Manel Esteller, Director of the Josep Carreras Leukemia Research Institute to talk about his work on Epigenetics and Epitranscriptomics in Cancer.
The focus of Manel Esteller's research career and the focus of his current team is to characterize the epigenome and epitranscriptome of cancer cells in comparison to healthy cells, and their interplay. Ultimately, their goal is to use this knowledge to develop new therapies for cancer. Key achievements from the Esteller lab began with the discovery of the first miRNA that undergoes specific cancer-methylation associated silencing. The team further identified many more miRNAs that also play a role in cancer. Next to miRNAs, Manel Esteller studied the influence of lncRNAs, enhancers and DNA methylation on cancer development and progression, insights that may be used to develop cancer biomarkers and potential treatments.
References
- Guil, S., Soler, M., Portela, A., Carrère, J., Fonalleras, E., Gómez, A., Villanueva, A., & Esteller, M. (2012). Intronic RNAs mediate EZH2 regulation of epigenetic targets. Nature Structural & Molecular Biology, 19(7), 664–670. https://doi.org/10.1038/nsmb.2315
- Vizoso, M., Ferreira, H. J., Lopez-Serra, P., Carmona, F. J., Martínez-Cardús, A., Girotti, M. R., Villanueva, A., Guil, S., Moutinho, C., Liz, J., Portela, A., Heyn, H., Moran, S., Vidal, A., Martinez-Iniesta, M., Manzano, J. L., Fernandez-Figueras, M. T., Elez, E., Muñoz-Couselo, E., … Esteller, M. (2015). Epigenetic activation of a cryptic TBC1D16 transcript enhances melanoma progression by targeting EGFR. Nature Medicine, 21(7), 741–750. https://doi.org/10.1038/nm.3863
- Agrelo, R., Cheng, W.-H., Setien, F., Ropero, S., Espada, J., Fraga, M. F., Herranz, M., Paz, M. F., Sanchez-Cespedes, M., Artiga, M. J., Guerrero, D., Castells, A., von Kobbe, C., Bohr, V. A., & Esteller, M. (2006). Epigenetic inactivation of the premature aging Werner syndrome gene in human cancer. Proceedings of the National Academy of Sciences of the United States of America, 103(23), 8822–8827. https://doi.org/10.1073/pnas.0600645103
- Lopez-Serra, P., Marcilla, M., Villanueva, A., Ramos-Fernandez, A., Palau, A., Leal, L., Wahi, J. E., Setien-Baranda, F., Szczesna, K., Moutinho, C., Martinez-Cardus, A., Heyn, H., Sandoval, J., Puertas, S., Vidal, A., Sanjuan, X., Martinez-Balibrea, E., Viñals, F., Perales, J. C., … Esteller, M. (2014). A DERL3-associated defect in the degradation of SLC2A1 mediates the Warburg effect. Nature Communications, 5, 3608. https://doi.org/10.1038/ncomms4608
- Rosselló-Tortella, M., Llinàs-Arias, P., Sakaguchi, Y., Miyauchi, K., Davalos, V., Setien, F., Calleja-Cervantes, M. E., Piñeyro, D., Martínez-Gómez, J., Guil, S., Joshi, R., Villanueva, A., Suzuki, T., & Esteller, M. (2020). Epigenetic loss of the transfer RNA-modifying enzyme TYW2 induces ribosome frameshifts in colon cancer. Proceedings of the National Academy of Sciences of the United States of America, 117(34), 20785–20793. https://doi.org/10.1073/pnas.2003358117
- Castro de Moura, M., Davalos, V., Planas-Serra, L., Alvarez-Errico, D., Arribas, C., Ruiz, M., Aguilera-Albesa, S., Troya, J., Valencia-Ramos, J., Vélez-Santamaria, V., Rodríguez-Palmero, A., Villar-Garcia, J., Horcajada, J. P., Albu, S., Casasnovas, C., Rull, A., Reverte, L., Dietl, B., Dalmau, D., … Esteller, M. (2021). Epigenome-wide association study of COVID-19 severity with respiratory failure. EBioMedicine, 66, 103339. https://doi.org/10.1016/j.ebiom.2021.103339
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In this episode of the Epigenetics Podcast, we caught up with Yad Ghavi-Helm from the Institut de Génomique Functionnelle de Lyon to talk about her work on enhancer-promoter interactions during development.
The Laboratory of Yad Ghavi-Helm focuses on how developmental genes are regulated by enhancers. Their work shows that developmental genes are often regulated by more than one enhancer and that those enhancers can often be located many kilobases away on the linear chromosome. Furthermore, their research also indicates that the interactions between promoters and their respective enhancers are usually established before the expression of the target gene is switched on, and that those interactions are generally stable during embryogenesis. In addition, those stable interactions seem to coincide with paused RNA Pol II being located at those promoters before gene activation.
References
- Ghavi-Helm, Y., Michaut, M., Acker, J., Aude, J.-C., Thuriaux, P., Werner, M., & Soutourina, J. (2008). Genome-wide location analysis reveals a role of TFIIS in RNA polymerase III transcription. Genes & Development, 22(14), 1934–1947. https://doi.org/10.1101/gad.471908
- Ghavi-Helm, Y., Klein, F. A., Pakozdi, T., Ciglar, L., Noordermeer, D., Huber, W., & Furlong, E. E. M. (2014). Enhancer loops appear stable during development and are associated with paused polymerase. Nature, 512(7512), 96–100. https://doi.org/10.1038/nature13417
- Ghavi-Helm, Y., Jankowski, A., Meiers, S., Viales, R. R., Korbel, J. O., & Furlong, E. E. M. (2019). Highly rearranged chromosomes reveal uncoupling between genome topology and gene expression. Nature Genetics, 51(8), 1272–1282. https://doi.org/10.1038/s41588-019-0462-3
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In this episode of the Epigenetics Podcast, we caught up with Folami Ideraabdullah from the University of Chapel Hill to talk about her work on the environmental modulation of the epigenome during development.
The lab of Folami Ideraabdullah focuses on studying how environmental factors modulate the epigenome. In particular the team investigates how Vitamin D levels influence epigenetic processes and, hence, the susceptibility for diseases like adipositas. Folami Ideraabdullah started with a genome-wide screen of DNA Methylation patterns that are observed after Vitamin D depletion. This work was then followed up by investigating the impact of Vitamin D depletion on mouse sperm DNA methylation.
References
- Xue, J., Schoenrock, S. A., Valdar, W., Tarantino, L. M., & Ideraabdullah, F. Y. (2016). Maternal vitamin D depletion alters DNA methylation at imprinted loci in multiple generations. Clinical Epigenetics, 8(1), 107. https://doi.org/10.1186/s13148-016-0276-4
- Xue, J., Gharaibeh, R. Z., Pietryk, E. W., Brouwer, C., Tarantino, L. M., Valdar, W., & Ideraabdullah, F. Y. (2018). Impact of vitamin D depletion during development on mouse sperm DNA methylation. Epigenetics, 13(9), 959–974. https://doi.org/10.1080/15592294.2018.1526027
- Xue, J., Hutchins, E. K., Elnagheeb, M., Li, Y., Valdar, W., McRitchie, S., Sumner, S., & Ideraabdullah, F. Y. (2020). Maternal Liver Metabolic Response to Chronic Vitamin D Deficiency Is Determined by Mouse Strain Genetic Background. Current Developments in Nutrition, 4(8), nzaa106. https://doi.org/10.1093/cdn/nzaa106
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In this episode of the Epigenetics Podcast, we caught up with Jane Mellor from the University of Oxford to talk about her work on H3K4me3, SET proteins, Isw1 and their role in transcription.
Since the beginning of the century, Jane Mellor and her team have focused on H3K4 trimethylation and the factors that influence this mark. They discovered that H3K4me3 is an almost universal mark of the first nucleosome in every transcribed unit and all organisms. She could subsequently, together with the Kouzarides lab, identify SetD1, the enzyme that is responsible for writing this modification. Later on, the team characterized Isw1, a chromatin remodeler which “reads” H3K4me3. More recently the lab focuses on how the polymerase transcribes throughout the first nucleosomes of the transcribed region at the +2 nucleosome, with the help of Spt4.
References
- Santos-Rosa, H., Schneider, R., Bannister, A. J., Sherriff, J., Bernstein, B. E., Emre, N. C. T., Schreiber, S. L., Mellor, J., & Kouzarides, T. (2002). Active genes are tri-methylated at K4 of histone H3. Nature, 419(6905), 407–411. https://doi.org/10.1038/nature01080
- Morillon, A., O’Sullivan, J., Azad, A., Proudfoot, N., & Mellor, J. (2003). Regulation of Elongating RNA Polymerase II by Forkhead Transcription Factors in Yeast. Science, 300(5618), 492–495. https://doi.org/10.1126/science.1081379
- Morillon, A., Karabetsou, N., O’Sullivan, J., Kent, N., Proudfoot, N., & Mellor, J. (2003). Isw1 Chromatin Remodeling ATPase Coordinates Transcription Elongation and Termination by RNA Polymerase II. Cell, 115(4), 425–435. https://doi.org/10.1016/S0092-8674(03)00880-8
- Uzun, Ü., Brown, T., Fischl, H., Angel, A., & Mellor, J. (2021). Spt4 facilitates the movement of RNA polymerase II through the +2 nucleosomal barrier. Cell Reports, 36(13), 109755. https://doi.org/10.1016/j.celrep.2021.109755
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In this episode of the Epigenetics Podcast, we caught up with Katja Kobow from the Universitätsklinikum Erlangen to talk about her work on the role of DNA methylation in Epilepsy.
Katja Kobow started studying the role of Epigenetics in Epilepsy by doing a genome wide Bisulfite-Sequencing screen that revealed a typical DNA methylation signature of epileptic patients versus healthy controls. After these initial results in human patient samples, she switched to an animal model to investigate this further. Now the focus of the Kobow Lab is to look for the same DNA methylation signature in blood samples, using this as a basis for the development of a potential prognostic marker for Epilepsy.
References
- Jablonski, Janos, Lucas Hoffmann, Ingmar Blümcke, Anna Fejtová, Steffen Uebe, Arif B. Ekici, Vadym Gnatkovsky, and Katja Kobow. 2021. “Experimental Epileptogenesis in a Cell Culture Model of Primary Neurons from Rat Brain: A Temporal Multi-Scale Study.” Cells 10(11):3004. doi: 10.3390/cells10113004.
- Jablonski, Janos, Lucas Hoffmann, Ingmar Blümcke, Anna Fejtová, Steffen Uebe, Arif B. Ekici, Vadym Gnatkovsky, and Katja Kobow. 2021. “Experimental Epileptogenesis in a Cell Culture Model of Primary Neurons from Rat Brain: A Temporal Multi-Scale Study.” Cells 10(11):3004. doi: 10.3390/cells10113004.
- Kobow, Katja, Mark Ziemann, Harikrishnan Kaipananickal, Ishant Khurana, Angelika Mühlebner, Martha Feucht, Johannes A. Hainfellner, Thomas Czech, Eleonora Aronica, Tom Pieper, Hans Holthausen, Manfred Kudernatsch, Hajo Hamer, Burkhard S. Kasper, Karl Rössler, Valerio Conti, Renzo Guerrini, Roland Coras, Ingmar Blümcke, Assam El‐Osta, and Antony Kaspi. 2019. “Genomic DNA Methylation Distinguishes Subtypes of Human Focal Cortical Dysplasia.” Epilepsia 60(6):1091–1103. doi: 10.1111/epi.14934.
- Dębski, Konrad J., Asla Pitkanen, Noora Puhakka, Anna M. Bot, Ishant Khurana, Kn Harikrishnan, Mark Ziemann, Antony Kaspi, Assam El-Osta, Katarzyna Lukasiuk, and Katja Kobow. 2016. “Etiology Matters – Genomic DNA Methylation Patterns in Three Rat Models of Acquired Epilepsy.” Scientific Reports 6(1):25668. doi: 10.1038/srep25668.
- Kobow, Katja, Antony Kaspi, K. N. Harikrishnan, Katharina Kiese, Mark Ziemann, Ishant Khurana, Ina Fritzsche, Jan Hauke, Eric Hahnen, Roland Coras, Angelika Mühlebner, Assam El-Osta, and Ingmar Blümcke. 2013. “Deep Sequencing Reveals Increased DNA Methylation in Chronic Rat Epilepsy.” Acta Neuropathologica 126(5):741–56. doi: 10.1007/s00401-013-1168-8.
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In this episode of the Epigenetics Podcast, we caught up with Emily Bernstein from Icahn Schoon of Medicine at Mount Sinai to talk about her work on MacroH2A function and the role of Polycomb proteins in its epigenetic regulation, and how this affects in stem cell development and disease.
The Bernstein Lab focuses on histone variants, in particular the H2A variant macroH2A. Chromatin architecture is influenced by the composition of the nucleosome and, hence, exchanging the core histones for histone variants can have a major impact on chromatin structure. MacroH2A variantsare the most unique histone variants due to a 30kDa non-histone domain (macro domain) at their C-termini. This macro domain likely confers important functions to macroH2A variants, which have important regulatory roles in the cell. Among other things, the Bernstein Lab has shown that macroH2A is enriched at a critical set of Utx target genes whose expression is critical for the early stages of induced pluripotency, and that macroH2A plays a role as a barrier to tumorigenesis.
References
- Kapoor, A., Goldberg, M. S., Cumberland, L. K., Ratnakumar, K., Segura, M. F., Emanuel, P. O., Menendez, S., Vardabasso, C., LeRoy, G., Vidal, C. I., Polsky, D., Osman, I., Garcia, B. A., Hernando, E., & Bernstein, E. (2010). The histone variant macroH2A suppresses melanoma progression through regulation of CDK8. Nature, 468(7327), 1105–1109. https://doi.org/10.1038/nature09590
- Vardabasso, C., Gaspar-Maia, A., Hasson, D., Pünzeler, S., Valle-Garcia, D., Straub, T., Keilhauer, E. C., Strub, T., Dong, J., Panda, T., Chung, C.-Y., Yao, J. L., Singh, R., Segura, M. F., Fontanals-Cirera, B., Verma, A., Mann, M., Hernando, E., Hake, S. B., & Bernstein, E. (2015). Histone Variant H2A.Z.2 Mediates Proliferation and Drug Sensitivity of Malignant Melanoma. Molecular Cell, 59(1), 75–88. https://doi.org/10.1016/j.molcel.2015.05.009
- Sun, Zhen, Dan Filipescu, Joshua Andrade, Alexandre Gaspar-Maia, Beatrix Ueberheide, and Emily Bernstein. 2018. “Transcription-Associated Histone Pruning Demarcates MacroH2A Chromatin Domains.” Nature Structural & Molecular Biology 25(10):958–70. doi: 10.1038/s41594-018-0134-5.
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- Influence of Histone Variants on Chromatin Structure and Metabolism (Marcus Buschbeck)
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In this episode of the Epigenetics Podcast, we caught up with Jane Skok from New York University School of Medicine to talk about her work on spatio-temporal alterations in chromosome dynamics.
Studies demonstrating that nuclear organization and long-range chromatin interactions play essential roles in gene regulation have been the focus of the Skok Lab, where the team has played a leading role. Their initial studies focused on lymphocyte development and the control of V(D)J recombination, a key part of generating the diverse repertoire of B-cell antibodies and T-cell receptors. The Skok Lab was among the first to demonstrate the possibility of chromatin forming dynamic loops which lead to the formation of reversible intra-locus loops in the immunoglobulin and T-cell receptor loci and to a profound impact on the ability of B and T cells to generate receptor diversity.
References
- Roldán, E., Fuxa, M., Chong, W., Martinez, D., Novatchkova, M., Busslinger, M., & Skok, J. A. (2005). Locus “decontraction” and centromeric recruitment contribute to allelic exclusion of the immunoglobulin heavy-chain gene. Nature Immunology, 6(1), 31–41. https://doi.org/10.1038/ni1150
- Skok, J. A. (2014). Taking a break from the lab: Can it really be done? Trends in Cell Biology, 24(12), 725–726. https://doi.org/10.1016/j.tcb.2014.09.002
- Proudhon, C., Snetkova, V., Raviram, R., Lobry, C., Badri, S., Jiang, T., Hao, B., Trimarchi, T., Kluger, Y., Aifantis, I., Bonneau, R., & Skok, J. A. (2016). Active and Inactive Enhancers Cooperate to Exert Localized and Long-Range Control of Gene Regulation. Cell Reports, 15(10), 2159–2169. https://doi.org/10.1016/j.celrep.2016.04.087
- Lhoumaud, P., Sethia, G., Izzo, F., Sakellaropoulos, T., Snetkova, V., Vidal, S., Badri, S., Cornwell, M., Di Giammartino, D. C., Kim, K.-T., Apostolou, E., Stadtfeld, M., Landau, D. A., & Skok, J. (2019). EpiMethylTag: Simultaneous detection of ATAC-seq or ChIP-seq signals with DNA methylation. Genome Biology, 20(1), 248. https://doi.org/10.1186/s13059-019-1853-6
- Nishana, M., Ha, C., Rodriguez-Hernaez, J., Ranjbaran, A., Chio, E., Nora, E. P., Badri, S. B., Kloetgen, A., Bruneau, B. G., Tsirigos, A., & Skok, J. A. (2020). Defining the relative and combined contribution of CTCF and CTCFL to genomic regulation. Genome Biology, 21(1), 108. https://doi.org/10.1186/s13059-020-02024-0
Related Episodes
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- Chromatin Organization (Susan Gasser)
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In this episode of the Epigenetics Podcast, we caught up with Marieke Oudelaar from the Max Planck Institute for Biophysical Chemistry to talk about her work on chromatin organization during development and disease.
Marieke Oudelaar and her team focus on on developing high-resolution Chromosome Conformation Capture (3C) based techniques, like low-input Capture-C, Tri-C, and Tiled-C. Those techniques are then used in combination with other genomic techniques, genetic perturbations, and computational approaches to investigate the 3D structure of chromatin in development and disease. The team focused on the interplay between genome organisation and regulation during mammalian differentiation, and how perturbations in these processes contribute to human disease, including cancer.
References
- Oudelaar, A. M., Davies, J. O. J., Downes, D. J., Higgs, D. R., & Hughes, J. R. (2017). Robust detection of chromosomal interactions from small numbers of cells using low-input Capture-C. Nucleic Acids Research, 45(22), e184–e184. https://doi.org/10.1093/nar/gkx1194
- Oudelaar, A. M., Davies, J. O. J., Hanssen, L. L. P., Telenius, J. M., Schwessinger, R., Liu, Y., Brown, J. M., Downes, D. J., Chiariello, A. M., Bianco, S., Nicodemi, M., Buckle, V. J., Dekker, J., Higgs, D. R., & Hughes, J. R. (2018). Single-allele chromatin interactions identify regulatory hubs in dynamic compartmentalized domains. Nature Genetics, 50(12), 1744–1751. https://doi.org/10.1038/s41588-018-0253-2
- Oudelaar, A. M., Beagrie, R. A., Gosden, M., de Ornellas, S., Georgiades, E., Kerry, J., Hidalgo, D., Carrelha, J., Shivalingam, A., El-Sagheer, A. H., Telenius, J. M., Brown, T., Buckle, V. J., Socolovsky, M., Higgs, D. R., & Hughes, J. R. (2020). Dynamics of the 4D genome during in vivo lineage specification and differentiation. Nature Communications, 11(1), 2722. https://doi.org/10.1038/s41467-020-16598-7
- Aljahani, A., Hua, P., Karpinska, M. A., Quililan, K., Davies, J. O. J., & Oudelaar, A. M. (2021). Analysis of sub-kilobase chromatin topology reveals nano-scale regulatory interactions with variable dependence on cohesin and CTCF [Preprint]. Genomics. https://doi.org/10.1101/2021.08.10.455796
Related Episodes
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In this episode of the Epigenetics Podcast, we caught up with Camila dos Santos from Cold Spring Harbor Laboratories to talk about her work on enhancers and chromatin remodeling in mammary gland development.
The lab of Camila dos Santos focuses on epigenetic regulation of normal and malignant mammary gland development. After puberty, the next significant phase in mammary gland development occurs in pregnancy, including changes in cellular function, and tissue reorganization. A different and as significant change in mammary glands occurs in the development breast cancer.
Camila dos Santos and her lab were recently able to show that the reaction of mammary glands to a second pregnancy is different than to a first one, which is accompanied by changes in the DNA methylome of the cells. Furthermore, the lab studies the connection of pregnancy-induced epigenetic changes of chromatin and the risk of cancer development.
References
- dos Santos, C. O., Rebbeck, C., Rozhkova, E., Valentine, A., Samuels, A., Kadiri, L. R., Osten, P., Harris, E. Y., Uren, P. J., Smith, A. D., & Hannon, G. J. (2013). Molecular hierarchy of mammary differentiation yields refined markers of mammary stem cells. Proceedings of the National Academy of Sciences, 110(18), 7123–7130. https://doi.org/10.1073/pnas.1303919110
- dos Santos, C. O., Dolzhenko, E., Hodges, E., Smith, A. D., & Hannon, G. J. (2015). An Epigenetic Memory of Pregnancy in the Mouse Mammary Gland. Cell Reports, 11(7), 1102–1109. https://doi.org/10.1016/j.celrep.2015.04.015
- Feigman, M. J., Moss, M. A., Chen, C., Cyrill, S. L., Ciccone, M. F., Trousdell, M. C., Yang, S.-T., Frey, W. D., Wilkinson, J. E., & dos Santos, C. O. (2020). Pregnancy reprograms the epigenome of mammary epithelial cells and blocks the development of premalignant lesions. Nature Communications, 11(1), 2649. https://doi.org/10.1038/s41467-020-16479-z
Related Episodes
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- Epigenetic Regulation of Stem Cell Self-Renewal and Differentiation (Peggy Goodell)
- Cancer and Epigenetics (David Jones)
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In this episode of the Epigenetics Podcast, we caught up with Marnie Blewitt from the Walter and Eliza Hall Institute of Medical Research to talk about her work on the role of SMCHD1 in Development and Disease.
The Laboratory of Marnie Blewitt focuses finding inhibitors or activators for the epigenetic regulator SMCHD1. Marnie Blewitt identified and characterized this protein during her PhD and the findings were published in 2008 in Nature Genetics. Since then, she and her team were able to investigate the function of this protein further. By doing so, they showed the involvement of SMCHD1 in cancer and several other diseases. Currently the lab is screening for small molecules that can act as inhibitors or activators of SMCHD1 the former as potential treatments for facioscapulohumeral muscular dystrophy, the latter for Prader Willi and Schaaf-Yang syndromes, both of which have no current targeted treatments.
References
- Blewitt, M. E., Gendrel, A.-V., Pang, Z., Sparrow, D. B., Whitelaw, N., Craig, J. M., Apedaile, A., Hilton, D. J., Dunwoodie, S. L., Brockdorff, N., Kay, G. F., & Whitelaw, E. (2008). SmcHD1, containing a structural-maintenance-of-chromosomes hinge domain, has a critical role in X inactivation. Nature Genetics, 40(5), 663–669. https://doi.org/10.1038/ng.142
- Leong, H. S., Chen, K., Hu, Y., Lee, S., Corbin, J., Pakusch, M., Murphy, J. M., Majewski, I. J., Smyth, G. K., Alexander, W. S., Hilton, D. J., & Blewitt, M. E. (2013). Epigenetic Regulator Smchd1 Functions as a Tumor Suppressor. Cancer Research, 73(5), 1591–1599. https://doi.org/10.1158/0008-5472.CAN-12-3019
- Gordon, C. T., Xue, S., Yigit, G., Filali, H., Chen, K., Rosin, N., Yoshiura, K., Oufadem, M., Beck, T. J., McGowan, R., Magee, A. C., Altmüller, J., Dion, C., Thiele, H., Gurzau, A. D., Nürnberg, P., Meschede, D., Mühlbauer, W., Okamoto, N., … Reversade, B. (2017). De novo mutations in SMCHD1 cause Bosma arhinia microphthalmia syndrome and abrogate nasal development. Nature Genetics, 49(2), 249–255. https://doi.org/10.1038/ng.3765
Related Episodes
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- Biophysical Modeling of 3-D Genome Organization (Leonid Mirny)
- Unraveling Mechanisms of Chromosome Formation (Job Dekker)
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In this episode of the Epigenetics Podcast, we caught up with Efrat Shema from the Weizmann Institute of Science to talk about her work on Single Molecule Imaging of chromatin, and the analysis of nucleosomes circulating in plasma.
In ChIP-Seq experiments the peak you get as a read out represents an average over, most often, millions of cells. Furthermore, one often does not know if that peak represents one or more than one nucleosome. If you then want to study multiple marks at the same time, the question remains: do those modifications occur at the same time, in the same cell?
The Laboratory of Efrat Shema works on answering those questions by developing methods to study the modification patterns on single nucleosomes with single molecule imaging. With that it is possible to study single nucleosomes in a high throughout manner to identify the modifications they are decorated with. A subsequent sequencing step makes it possible to identify the genomic location of that nucleosome.
References
- Shema, E., Bernstein, B. E., & Buenrostro, J. D. (2019). Single-cell and single-molecule epigenomics to uncover genome regulation at unprecedented resolution. Nature Genetics, 51(1), 19–25. https://doi.org/10.1038/s41588-018-0290-x
- Shema, E., Jones, D., Shoresh, N., Donohue, L., Ram, O., & Bernstein, B. E. (2016). Single-molecule decoding of combinatorially modified nucleosomes. Science, 352(6286), 717–721. https://doi.org/10.1126/science.aad7701
- Shema, E., Kim, J., Roeder, R. G., & Oren, M. (2011). RNF20 Inhibits TFIIS-Facilitated Transcriptional Elongation to Suppress Pro-oncogenic Gene Expression. Molecular Cell, 42(4), 477–488. https://doi.org/10.1016/j.molcel.2011.03.011
- Shema, E., Tirosh, I., Aylon, Y., Huang, J., Ye, C., Moskovits, N., Raver-Shapira, N., Minsky, N., Pirngruber, J., Tarcic, G., Hublarova, P., Moyal, L., Gana-Weisz, M., Shiloh, Y., Yarden, Y., Johnsen, S. A., Vojtesek, B., Berger, S. L., & Oren, M. (2008). The histone H2B-specific ubiquitin ligase RNF20/hBRE1 acts as a putative tumor suppressor through selective regulation of gene expression. Genes & Development, 22(19), 2664–2676. https://doi.org/10.1101/gad.1703008
Related Episodes
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- The Past, Present, and Future of Epigenetics (Joe Fernandez, founder of Active Motif)
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In this episode of the Epigenetics Podcast, we caught up with Serena Sanulli from Stanford University to talk about her work on Heterochromatin Protein 1 (HP1), the structure of chromatin on the atomic-scale and the meso-scale, and phase separation.
The Laboratory of Serena Sanulli is interested in finding connections between changes that happen on the nucleosomal level and the resulting impact on chromatin conformation on the meso-scale. They combine methods like NMR and Hydrogen-Deuterium Exchange-MS with Cell Biology and Genetics. This enables them to dissect how cells use the diverse biophysical properties of chromatin to regulate gene expression across length and time scales.
A second focus of the lab is HP1, which interacts with the nucleosome and changes its conformation, enabling the compaction of the genome into heterochromatin, effectively silencing genes in that region. A high concentration of HP1 leads to the phenomenon of phase separation in the nucleus, which the Sanulli lab is now investigating.
References
- Sanulli, S., Justin, N., Teissandier, A., Ancelin, K., Portoso, M., Caron, M., Michaud, A., Lombard, B., da Rocha, S. T., Offer, J., Loew, D., Servant, N., Wassef, M., Burlina, F., Gamblin, S. J., Heard, E., & Margueron, R. (2015). Jarid2 Methylation via the PRC2 Complex Regulates H3K27me3 Deposition during Cell Differentiation. Molecular Cell, 57(5), 769–783. https://doi.org/10.1016/j.molcel.2014.12.020
- Sanulli, S., Trnka, M. J., Dharmarajan, V., Tibble, R. W., Pascal, B. D., Burlingame, A. L., Griffin, P. R., Gross, J. D., & Narlikar, G. J. (2019). HP1 reshapes nucleosome core to promote phase separation of heterochromatin. Nature, 575(7782), 390–394. https://doi.org/10.1038/s41586-019-1669-2
- Sanulli, S., & Narlikar, G. J. (2021). Generation and Biochemical Characterization of Phase‐Separated Droplets Formed by Nucleic Acid Binding Proteins: Using HP1 as a Model System. Current Protocols, 1(5). https://doi.org/10.1002/cpz1.109
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- Heterochromatin and Phase Separation (Gary Karpen)
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In this episode of the Epigenetics Podcast, we caught up with Catherine Jensen Peña from Princeton University to talk about her work on early life stress and its effects on behavior.
The Laboratory of Catherine Peña focuses on how early life experiences are encoded and maintained into adulthood, with a long-lasting impact on behavior. Recent work showed, that child maltreatment and other forms of early life stress increase the lifetime risk of depression and other mood, anxiety, and drug disorders by 2-4 fold. The Peña Lab uses genome wide approaches to investigate key brain regions with a two-hit stress model.
Using RNA-Seq, the Peña Lab has shown that depression-like gene expression patterns are programmed by early life stress, similar to observations in mice exhibiting depression-like behavior after adult stress and are visible even before behavioral changes. Furthermore, latent and unique transcriptional responses to adult stress among a subset of genes is programmed by early life stress. The role of chromatin modifications in regulating these processes are investigated using state of the art technologies like Mod-Spec or ATAC-Seq.
References
- Kronman, H., Torres-Berrío, A., Sidoli, S., Issler, O., Godino, A., Ramakrishnan, A., Mews, P., Lardner, C. K., Parise, E. M., Walker, D. M., van der Zee, Y. Y., Browne, C. J., Boyce, B. F., Neve, R., Garcia, B. A., Shen, L., Peña, C. J., & Nestler, E. J. (2021). Long-term behavioral and cell-type-specific molecular effects of early life stress are mediated by H3K79me2 dynamics in medium spiny neurons. Nature Neuroscience, 24(5), 667–676. https://doi.org/10.1038/s41593-021-00814-8
- Peña, C. J., Smith, M., Ramakrishnan, A., Cates, H. M., Bagot, R. C., Kronman, H. G., Patel, B., Chang, A. B., Purushothaman, I., Dudley, J., Morishita, H., Shen, L., & Nestler, E. J. (2019). Early life stress alters transcriptomic patterning across reward circuitry in male and female mice. Nature Communications, 10(1), 5098. https://doi.org/10.1038/s41467-019-13085-6
- Peña, C. J., Kronman, H. G., Walker, D. M., Cates, H. M., Bagot, R. C., Purushothaman, I., Issler, O., Loh, Y.-H. E., Leong, T., Kiraly, D. D., Goodman, E., Neve, R. L., Shen, L., & Nestler, E. J. (2017). Early life stress confers lifelong stress susceptibility in mice via ventral tegmental area OTX2. Science, 356(6343), 1185–1188. https://doi.org/10.1126/science.aan4491
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In this episode of the Epigenetics Podcast, we caught up with Ali Shilatifard from Northwestern University to talk about his work on targeting COMPASS to cure childhood leukemia.
The Shilatifard Lab studies childhood leukemia and how it can potentially be treated using epigenetic targets. The team focuses on is SET1/COMPASS, a histone H3 lysine4 methylase. Ali Shilatifard was able to purify and identify its activity, with results published in 2001 in PNAS. This protein complex is conserved from yeast to drosophila to humans.
Surprisingly, the Shilatifard Team could show that the catalytic activity of COMPASS is not necessary for viability of drosophila. Furthermore, they found that catalytic activity was not the decisive feature of the complex, but rather its role in the context of chromatin structure, in particular a protein domain that only spans 80 amino acids within the 4000 amino acid protein.
References
- Miller, T., Krogan, N. J., Dover, J., Erdjument-Bromage, H., Tempst, P., Johnston, M., Greenblatt, J. F., & Shilatifard, A. (2001). COMPASS: A complex of proteins associated with a trithorax-related SET domain protein. Proceedings of the National Academy of Sciences, 98(23), 12902–12907. https://doi.org/10.1073/pnas.231473398
- Lin, C., Garruss, A. S., Luo, Z., Guo, F., & Shilatifard, A. (2013). The RNA Pol II Elongation Factor Ell3 Marks Enhancers in ES Cells and Primes Future Gene Activation. Cell, 152(1–2), 144–156. https://doi.org/10.1016/j.cell.2012.12.015
- Wang, L., Zhao, Z., Ozark, P. A., Fantini, D., Marshall, S. A., Rendleman, E. J., Cozzolino, K. A., Louis, N., He, X., Morgan, M. A., Takahashi, Y., Collings, C. K., Smith, E. R., Ntziachristos, P., Savas, J. N., Zou, L., Hashizume, R., Meeks, J. J., & Shilatifard, A. (2018). Resetting the epigenetic balance of Polycomb and COMPASS function at enhancers for cancer therapy. Nature Medicine, 24(6), 758–769. https://doi.org/10.1038/s41591-018-0034-6
- Morgan, M. A. J., & Shilatifard, A. (2020). Reevaluating the roles of histone-modifying enzymes and their associated chromatin modifications in transcriptional regulation. Nature Genetics, 52(12), 1271–1281. https://doi.org/10.1038/s41588-020-00736-4
Related Episodes
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In this episode of the Epigenetics Podcast, we caught up with Yael David from Memorial Sloan Kettering Cancer Center in New York to talk about her work on Effects of Non-Enzymatic Covalent Histone Modifications on Chromatin.
The David lab studies on non-enzymatic covalent modifications of Histones, including Histone glycation and citrullination. These modifications recognize metabolites that are produced in the cell and aid as a sensor for chromatin to quickly adapt to cellular changes. These unique modifications do not have a so-called erasing enzyme, which makes them terminal, rendering these sites inaccessible for further modifications such as methylation or acetylation.
A second area of research in the David lab is Histone H1. The lab has developed a new method to purify Histone H1, superior to the commonly used method of acid extraction which leads to degradation of Histone H1. This purification method enabled the lab to purify and characterize the functional properties of all Histone H1 variants.
References
- David, Y., Vila-Perelló, M., Verma, S., & Muir, T. W. (2015). Chemical tagging and customizing of cellular chromatin states using ultrafast trans -splicing inteins. Nature Chemistry, 7(5), 394–402. https://doi.org/10.1038/nchem.2224
- David, Y., & Muir, T. W. (2017). Emerging Chemistry Strategies for Engineering Native Chromatin. Journal of the American Chemical Society, 139(27), 9090–9096. https://doi.org/10.1021/jacs.7b03430
- Osunsade, A., Prescott, N. A., Hebert, J. M., Ray, D. M., Jmeian, Y., Lorenz, I. C., & David, Y. (2019). A Robust Method for the Purification and Characterization of Recombinant Human Histone H1 Variants. Biochemistry, 58(3), 171–176. https://doi.org/10.1021/acs.biochem.8b01060
- Zheng, Q., Omans, N. D., Leicher, R., Osunsade, A., Agustinus, A. S., Finkin-Groner, E., D’Ambrosio, H., Liu, B., Chandarlapaty, S., Liu, S., & David, Y. (2019). Reversible histone glycation is associated with disease-related changes in chromatin architecture. Nature Communications, 10(1), 1289. https://doi.org/10.1038/s41467-019-09192-z
- Zheng, Q., Osunsade, A., & David, Y. (2020). Protein arginine deiminase 4 antagonizes methylglyoxal-induced histone glycation. Nature Communications, 11(1), 3241. https://doi.org/10.1038/s41467-020-17066-y
Related Episodes
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- Influence of Histone Variants on Chromatin Structure and Metabolism (Marcus Buschbeck)
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In this episode of the Epigenetics Podcast, we caught up with Jason Buenrostro from Harvard University to talk about his work on developing biological tools to measure chromatin dynamics in single-cells. He explains how his lab uses these tools to study chromatin alterations in different cell types and disease states to uncover new mechanisms of gene regulation and their contribution to those diseases.
In his first years of his research career Jason Buenrostro took a risk and just added an enzyme called Transposase to cells in a cell culture. What he saw on a subsequent agarose gel astonished him. He was able to recreate a nucleosomal ladder that he knew from experiments using MNase or DNase-Seq, however, without the tedious steps of optimization. In the following years he optimized that method and data analyzation into a method known today as ATAC-Seq. In recent years he was also able to bring ATAC-Seq to the next level and developed single cell ATAC-Seq (scATAC-Seq), and combining it with RNA-Seq in a multi-omics approach.
In this Episode we discuss how Jason Buenrostro developed ATAC-Seq in William Greenleaf's lab, how a lack of equipment shaped the ATAC-Seq protocol, and how scATAC-Seq has enabled a whole different way of looking at biological samples.
References
- Buenrostro, J. D., Giresi, P. G., Zaba, L. C., Chang, H. Y., & Greenleaf, W. J. (2013). Transposition of native chromatin for fast and sensitive epigenomic profiling of open chromatin, DNA-binding proteins and nucleosome position. Nature Methods, 10(12), 1213–1218. https://doi.org/10.1038/nmeth.2688
- Buenrostro, J. D., Wu, B., Litzenburger, U. M., Ruff, D., Gonzales, M. L., Snyder, M. P., Chang, H. Y., & Greenleaf, W. J. (2015). Single-cell chromatin accessibility reveals principles of regulatory variation. Nature, 523(7561), 486–490. https://doi.org/10.1038/nature14590
- Buenrostro, J. D., Corces, M. R., Lareau, C. A., Wu, B., Schep, A. N., Aryee, M. J., Majeti, R., Chang, H. Y., & Greenleaf, W. J. (2018). Integrated Single-Cell Analysis Maps the Continuous Regulatory Landscape of Human Hematopoietic Differentiation. Cell, 173(6), 1535-1548.e16. https://doi.org/10.1016/j.cell.2018.03.074
- Lareau, C. A., Duarte, F. M., Chew, J. G., Kartha, V. K., Burkett, Z. D., Kohlway, A. S., Pokholok, D., Aryee, M. J., Steemers, F. J., Lebofsky, R., & Buenrostro, J. D. (2019). Droplet-based combinatorial indexing for massive-scale single-cell chromatin accessibility. Nature Biotechnology, 37(8), 916–924. https://doi.org/10.1038/s41587-019-0147-6
Related Episodes
- Chromatin Profiling: From ChIP to CUT&RUN, CUT&Tag and CUTAC (Steven Henikoff)
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- Multiple Challenges in ChIP (Adam Blattler)
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In this episode of the Epigenetics Podcast, we caught up with Karmella Haynes from Emory University to talk about her work on synthetic chromatin epigenetics.
The Haynes lab focuses on the design of synthetic chromatin sensor proteins. The first one of this kind, the Polycomb Transcription Factor (PcTF), was published in 2011. It senses H3K27me3 and recruits effector proteins to the sites of this modification. This sensor can be brought into cancer cells to activate hundreds of silenced genes. The lab now focuses on characterizing the effects of these sensor proteins genome wide, and seeks to find a way to deliver those sensor into cancer cells, without affecting healthy cells.
In this Episode we discuss how Karmella Haynes got into the field of Epigenetics, how she designed the PcTF sensor proteins, and the way she came to learn how important the right control experiments are. In the end we also discuss her activities to promote diversity and inclusion in science.
References
- Haynes, K. A., & Silver, P. A. (2011). Synthetic Reversal of Epigenetic Silencing. Journal of Biological Chemistry, 286(31), 27176–27182. https://doi.org/10.1074/jbc.C111.229567
- Haynes, K. A., Ceroni, F., Flicker, D., Younger, A., & Silver, P. A. (2012). A Sensitive Switch for Visualizing Natural Gene Silencing in Single Cells. ACS Synthetic Biology, 1(3), 99–106. https://doi.org/10.1021/sb3000035
- Daer, R. M., Cutts, J. P., Brafman, D. A., & Haynes, K. A. (2017). The Impact of Chromatin Dynamics on Cas9-Mediated Genome Editing in Human Cells. ACS Synthetic Biology, 6(3), 428–438. https://doi.org/10.1021/acssynbio.5b00299
- Tekel, S. J., & Haynes, K. A. (2017). Molecular structures guide the engineering of chromatin. Nucleic Acids Research, 45(13), 7555–7570. https://doi.org/10.1093/nar/gkx531
- Tekel, S. J., Vargas, D. A., Song, L., LaBaer, J., Caplan, M. R., & Haynes, K. A. (2018). Tandem Histone-Binding Domains Enhance the Activity of a Synthetic Chromatin Effector. ACS Synthetic Biology, 7(3), 842–852. https://doi.org/10.1021/acssynbio.7b00281
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In this episode of the Epigenetics Podcast, we caught up with Enrico Glaab from the University of Luxemburg to talk about his work on the development of integrative machine learning tools for neurodegenerative diseases.
The work of Dr. Enrico Glaab focuses on neurodegenerative disorders like Parkinson’s and Alzheimer’s disease. In his group his team works on the development of software tools to analyze molecular, clinical and neuroimaging data for those diseases that can be used and applied easily by scientists and deliver publication ready figures. More recently, Enrico Glaab's group got interested in the influence of Epigenetics in Parkinson's and Alzheimer's disease.
In this Episode we discuss how Enrico Glaab made the switch from wet-lab to becoming a bioinformatician and how he uses integrative machine learning tools to find approaches to not only cure but also be able to detect neurodegenerative diseases like Alzheimer's or Parkinson's early on.
References
- Enrico Glaab, Reinhard Schneider (2015) RepExplore: addressing technical replicate variance in proteomics and metabolomics data analysis (Bioinformatics) DOI: 10.1093/bioinformatics/btv127
- Enrico Glaab, Reinhard Schneider (2015) Comparative pathway and network analysis of brain transcriptome changes during adult aging and in Parkinson’s disease (Neurobiology of Disease) DOI: 10.1016/j.nbd.2014.11.002
- Sandra Köglsberger, Maria Lorena Cordero-Maldonado, … Enrico Glaab (2017) Gender-Specific Expression of Ubiquitin-Specific Peptidase 9 Modulates Tau Expression and Phosphorylation: Possible Implications for Tauopathies (Molecular Neurobiology) DOI: 10.1007/s12035-016-0299-z
- Enrico Glaab, Paul Antony, … Manuel Buttini (2019) Transcriptome profiling data reveals ubiquitin-specific peptidase 9 knockdown effects (Data in Brief) DOI: 10.1016/j.dib.2019.104130
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In this episode of the Epigenetics Podcast, we caught up with Diane Dickel from Lawrence Berkeley National Laboratory to talk about her work on ultraconserved enhancers and enhancer redundancy.
Diane Dickel and her co-workers study non-coding regions of the genome that harbor distant-acting transcriptional regulatory regions, called enhancers. Enhancers have been shown to be critical for normal embryonic development, implying evolutional conservation. Diane Dickel and her team try to identify and characterize enhancers at a genomic scale. Their efforts include the use of CRISPR/CAS9 to mutate enhancer sequences in order to understand sequence dependent functional relevance.
In this episode we discuss the function of ultraconserved enhancers, what ultraconservation actually means, how enhancer redundancy works and how Diane Dickel dealt with a failed PhD project.
References
- Dickel, D. E., Ypsilanti, A. R., Pla, R., Zhu, Y., Barozzi, I., Mannion, B. J., Khin, Y. S., Fukuda-Yuzawa, Y., Plajzer-Frick, I., Pickle, C. S., Lee, E. A., Harrington, A. N., Pham, Q. T., Garvin, T. H., Kato, M., Osterwalder, M., Akiyama, J. A., Afzal, V., Rubenstein, J. L. R., … Visel, A. (2018). Ultraconserved Enhancers Are Required for Normal Development. Cell, 172(3), 491-499.e15. https://doi.org/10.1016/j.cell.2017.12.017
- Gorkin, D. U., Barozzi, I., Zhao, Y., Zhang, Y., Huang, H., Lee, A. Y., Li, B., Chiou, J., Wildberg, A., Ding, B., Zhang, B., Wang, M., Strattan, J. S., Davidson, J. M., Qiu, Y., Afzal, V., Akiyama, J. A., Plajzer-Frick, I., Novak, C. S., … Ren, B. (2020). An atlas of dynamic chromatin landscapes in mouse fetal development. Nature, 583(7818), 744–751. https://doi.org/10.1038/s41586-020-2093-3
- Snetkova, V., Ypsilanti, A. R., Akiyama, J. A., Mannion, B. J., Plajzer-Frick, I., Novak, C. S., Harrington, A. N., Pham, Q. T., Kato, M., Zhu, Y., Godoy, J., Meky, E., Hunter, R. D., Shi, M., Kvon, E. Z., Afzal, V., Tran, S., Rubenstein, J. L. R., Visel, A., … Dickel, D. E. (2021). Ultraconserved enhancer function does not require perfect sequence conservation. Nature Genetics, 53(4), 521–528. https://doi.org/10.1038/s41588-021-00812-3
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In this episode of the Epigenetics Podcast, we caught up with Sandra Hake from the Justus Liebig University in Giessen to talk about her work on variants of core histones and their role as modulators of chromatin structure and function.
The overarching goal of Sandra Hake's research group is to understand how changes in chromatin structure and composition can influence various DNA-based processes, such as gene expression, repair of DNA damage, cell cycle progression, and genome stability. Their work deals with the study of histone variants which, together with DNA, represent the building blocks of the smallest chromatin components, the nucleosomes. They also investigate whether mutations and/or post-translational histone modifications and the deregulation of histone variant networks influence the emergence of diseases, especially the emergence of tumors.
In this episode we discuss how Sandra Hake approaches the characterization and identification of novel histone variants like H3.3, H3.X and H3.Y, what it's like to work in such a small field like histone variants, and what is coming up next for the Hake lab.
References
- Hake, S. B., Garcia, B. A., Duncan, E. M., Kauer, M., Dellaire, G., Shabanowitz, J., Bazett-Jones, D. P., Allis, C. D., & Hunt, D. F. (2006). Expression Patterns and Post-translational Modifications Associated with Mammalian Histone H3 Variants. Journal of Biological Chemistry, 281(1), 559–568. https://doi.org/10.1074/jbc.M509266200
- Wiedemann, S. M., Mildner, S. N., Bönisch, C., Israel, L., Maiser, A., Matheisl, S., Straub, T., Merkl, R., Leonhardt, H., Kremmer, E., Schermelleh, L., & Hake, S. B. (2010). Identification and characterization of two novel primate-specific histone H3 variants, H3.X and H3.Y. Journal of Cell Biology, 190(5), 777–791. https://doi.org/10.1083/jcb.201002043
- Bönisch, C., Schneider, K., Pünzeler, S., Wiedemann, S. M., Bielmeier, C., Bocola, M., Eberl, H. C., Kuegel, W., Neumann, J., Kremmer, E., Leonhardt, H., Mann, M., Michaelis, J., Schermelleh, L., & Hake, S. B. (2012). H2A.Z.2.2 is an alternatively spliced histone H2A.Z variant that causes severe nucleosome destabilization. Nucleic Acids Research, 40(13), 5951–5964. https://doi.org/10.1093/nar/gks267
- Link, S., Spitzer, R. M. M., Sana, M., Torrado, M., Völker-Albert, M. C., Keilhauer, E. C., Burgold, T., Pünzeler, S., Low, J. K. K., Lindström, I., Nist, A., Regnard, C., Stiewe, T., Hendrich, B., Imhof, A., Mann, M., Mackay, J. P., Bartkuhn, M., & Hake, S. B. (2018). PWWP2A binds distinct chromatin moieties and interacts with an MTA1-specific core NuRD complex. Nature Communications, 9(1), 4300. https://doi.org/10.1038/s41467-018-06665-5
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In this episode of the Epigenetics Podcast, we caught up with Déborah Bourc'his from L'Institut Curie in Paris to talk about her work on the role of DNA methylation in mammalian development.
During her postdoc years Déborah Bourc'his was able to characterize DNMT3L, a protein with unknown function at that time. It turned out that this protein is the cofactor responsible for stimulating DNA methylation activity in both the male and the female germline. Later on she discovered a novel DNA methylation enzyme called DNMT3C, which was unknown because it was not properly annotated, there was no sign of expression, and it was only expressed in male fetal germ cells. Furthermore, this enzyme only evolved in rodents, as a defense against young transposons.
In this episode we discuss the story behind how Déborah Bourc'his was able to discover and characterize the DNA methylation enzymes DNMT3L and DNMT3C and their role in mammalian development.
References
- R. Duffie, S. Ajjan, … D. Bourc’his (2014) The Gpr1/Zdbf2 locus provides new paradigms for transient and dynamic genomic imprinting in mammals (Genes & Development) DOI: 10.1101/gad.232058.113
- Natasha Zamudio, Joan Barau, … Déborah Bourc’his (2015) DNA methylation restrains transposons from adopting a chromatin signature permissive for meiotic recombination (Genes & Development) DOI: 10.1101/gad.257840.114](https://doi.org/10.1101/gad.257840.114)
- Marius Walter, Aurélie Teissandier, … Déborah Bourc’his (2016) An epigenetic switch ensures transposon repression upon dynamic loss of DNA methylation in embryonic stem cells (eLife) DOI: 10.7554/eLife.11418](https://doi.org/10.7554/eLife.11418)
- Joan Barau, Aurélie Teissandier, … Déborah Bourc’his (2016) The DNA methyltransferase DNMT3C protects male germ cells from transposon activity (Science (New York, N.Y.)) DOI: 10.1126/science.aah5143
- Maxim V. C. Greenberg, Juliane Glaser, … Déborah Bourc’his (2017) Transient transcription in the early embryo sets an epigenetic state that programs postnatal growth (Nature Genetics) DOI: 10.1038/ng.3718
- Roberta Ragazzini, Raquel Pérez-Palacios, … Raphaël Margueron (2019) EZHIP constrains Polycomb Repressive Complex 2 activity in germ cells (Nature Communications) DOI: 10.1038/s41467-019-11800-x
- Dura, M., Teissandier, A., Armand, M., Barau, J., Bonneville, L., Weber, M., Baudrin, L. G., Lameiras, S., & Bourc’his, D. (2021). DNMT3A-dependent DNA methylation is required for spermatogonial stem cells to commit to spermatogenesis [Preprint]. Developmental Biology. https://doi.org/10.1101/2021.04.19.440465
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In this episode of the Epigenetics Podcast, we caught up with Axel Imhof from the Ludwig Maximilian University of Munich in Germany to talk about his work on the identification of chromatin associated proteins using mass spectrometry.
As the head of the Proteomics Core Facility Axel Imhof collaborates with research groups around the world. In addition, in his own lab, he focuses on the assembly and composition of chromatin, how environmental metabolites influence epigenetic marks, and how chromatin factors can be used as markers for pathological states.
In this episode we discuss what has changed in the field of mass spectrometry over the years, how Axel Imhof takes advantage of collaborations, how metabolites influence chromatin, and how he is helping to bring epigenetic profiling via mass spectrometry to the clinic.
References
- Bonaldi, T., Regula, J. T., & Imhof, A. (2003). The Use of Mass Spectrometry for the Analysis of Histone Modifications. In Methods in Enzymology (Vol. 377, pp. 111–130). Elsevier. https://doi.org/10.1016/S0076-6879(03)77006-2
- Völker-Albert, M. C., Pusch, M. C., Fedisch, A., Schilcher, P., Schmidt, A., & Imhof, A. (2016). A Quantitative Proteomic Analysis of In Vitro Assembled Chromatin. Molecular & Cellular Proteomics, 15(3), 945–959. https://doi.org/10.1074/mcp.M115.053553
- Scharf, A. N. D., Meier, K., Seitz, V., Kremmer, E., Brehm, A., & Imhof, A. (2009). Monomethylation of Lysine 20 on Histone H4 Facilitates Chromatin Maturation. Molecular and Cellular Biology, 29(1), 57–67. https://doi.org/10.1128/MCB.00989-08
- Van den Ackerveken, P., Lobbens, A., Turatsinze, J.-V., Solis-Mezarino, V., Völker-Albert, M., Imhof, A., & Herzog, M. (2021). A novel proteomics approach to epigenetic profiling of circulating nucleosomes. Scientific Reports, 11(1), 7256. https://doi.org/10.1038/s41598-021-86630-3
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In this episode of the Epigenetics Podcast, we caught up with Steven Henikoff from the Fred Hutchinson Cancer Research Center in Seattle to talk about his work on Chromatin Profiling: From ChIP to CUT&RUN, CUT&Tag and CUTAC.
In the last few years Steven Henikoff has been developing methods which profile the chromatin landscape by using enzyme tethering. The quest first started with ChEC-Seq, which improved on Uli Laemmli's method of Chromatin endogenous cleavage (ChEC) but used sequencing as a read-out rather than southern blotting. Next, Cleavage Under Targets & Release Using Nuclease (CUT&RUN) was developed by making a fusion protein of Protein A and micrococcal nuclease (MNase), making it possible to achieve antibody-targeted cleavage of chromatin fragments. And finally, Cleavage Under Targets & Tagmenation (CUT&Tag) was developed by using Transposase Tn5 instead of MNase, which adds sequencing adapters and fragments chromatin at the same time, streamlining the protocol even further.
In this episode we discuss how working on centromeres set the stage for Steven Henikoff’s subsequent work, how he developed CUT&RUN and CUT&Tag, what the advantages and disadvantages of those methods are and how he developed all those experiments at home in his garage.
References
- Takehito Furuyama, Steven Henikoff (2009) Centromeric nucleosomes induce positive DNA supercoils (Cell) DOI: 10.1016/j.cell.2009.04.049
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Kristina Krassovsky, Jorja G. Henikoff, Steven Henikoff (2012) Tripartite organization of centromeric chromatin in budding yeast (Proceedings of the National Academy of Sciences of the United States of America) DOI: 10.1073/pnas.1118898109
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Jorja G. Henikoff, Jitendra Thakur, … Steven Henikoff (2015) A unique chromatin complex occupies young α-satellite arrays of human centromeres (Science Advances) DOI: 10.1126/sciadv.1400234
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Epigenomics Methods: ChEC-Seq, CUT&RUN, AutoCUT&RUN, Improved CUT&RUN, CUT&Tag, Automated CUT&Tag, CUTAC, scCUT&Tag.
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In this episode of the Epigenetics Podcast, we caught up with Charlotte Ling from Lund University in Sweden, to talk about her work on the role of DNA methylation in diabetes.
Dr. Charlotte Ling investigates how epigenetics influences diabetes, a major age-related disease that affects millions of people around the world. She and her team identified CpG-SNPs and differentially methylated DNA in human pancreatic islets, associated with Type 2 Diabetes. In addition, she explored the impact of a six-month exercise intervention plan on DNA methylation and health in middle-aged diabetic men.
Later-on, looking for useful applications for this knowledge, she determined blood-based biomarkers for diabetes and for successful treatment with Metformin, a common drug used for diabetes patients.
In this episode we discuss how Charlotte Ling ended up in the field of diabetes, how the success of her work impacted her ability to go on vacations, and how the results of her work are now used to develop blood-based biomarkers.
References
- Karl Bacos, Linn Gillberg, … Charlotte Ling (2016) Blood-based biomarkers of age-associated epigenetic changes in human islets associate with insulin secretion and diabetes (Nature Communications) DOI: 10.1038/ncomms11089
- Sonia García-Calzón, Alexander Perfilyev, … Charlotte Ling (2020) Epigenetic markers associated with metformin response and intolerance in drug-naïve patients with type 2 diabetes (Science Translational Medicine) DOI: 10.1126/scitranslmed.aaz1803
- Madhusudhan Bysani, Rasmus Agren, … Charlotte Ling (2019) ATAC-seq reveals alterations in open chromatin in pancreatic islets from subjects with type 2 diabetes (Scientific Reports) DOI: 10.1038/s41598-019-44076-8
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In this episode of the Epigenetics Podcast, we caught up with Monica Dus from the University of Michigan to talk about her work on nutriepigenetics and the effects of diet on behavior.
The focus of Monica Dus and her team is to study the effect of sugar on the brain and how diet has an effect on behavior. The Dus lab takes a multidisciplinary approach to answer questions like "What causes animals to overeat if they consume foods rich in sugar, salt, and fat?" and "How does such a diet alter the basic physiology and biochemistry of the brain to promote food intake and weight gain?" By doing this, they showed recently that the Polycomb Repressive Complex 2 (PRC2) plays a role in reprogramming the sensory neurons of Drosophila Melanogaster, reducing sweet sensation and hence promoting obesity when flies are fed a high sugar diet. In response to that diet the binding of PRC2 to chromatin in sweet gustatory neurons is altered and reshapes the developmental transcriptional network.
In this episode we discuss how flies taste food and sugar, how sugar modulates taste, and how a high sugar diet influences the taste and amount of food flies eat.
References
- Monica Dus, SooHong Min, … Greg S. B. Suh (2011) Taste-independent detection of the caloric content of sugar in Drosophila (Proceedings of the National Academy of Sciences of the United States of America) DOI: 10.1073/pnas.1017096108
- Christina E. May, Anoumid Vaziri, … Monica Dus (2019) High Dietary Sugar Reshapes Sweet Taste to Promote Feeding Behavior in Drosophila melanogaster (Cell Reports) DOI: 10.1016/j.celrep.2019.04.027
- Daniel Wilinski, Jasmine Winzeler, … Monica Dus (2019) Rapid metabolic shifts occur during the transition between hunger and satiety in Drosophila melanogaster (Nature Communications) DOI: 10.1038/s41467-019-11933-z
- Anoumid Vaziri, Morteza Khabiri, … Monica Dus (2020) Persistent epigenetic reprogramming of sweet taste by diet (Science Advances) DOI: 10.1126/sciadv.abc8492
- How to Science Podcast
- NeuroEpic Podcast
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In this episode of the Epigenetics Podcast, we caught up with Céline Vallot from L'Institut Curie in Paris to discuss her work on investigating the dynamics of epigenetic plasticity in cancer with single cell technologies.
During her Post-Doc years Céline Vallot worked on the inactive X chromosome. Using RNA-Seq she discovered a novel long noncoding RNA (lncRNA) called XACT. This lncRNA is expressed from and coats the active X chromosome in human pluripotent cells. Céline Vallot also showed that XACT is specific to humans and cannot be found in mice.
After starting her own lab, Céline Vallot began to focus on Single Cell Epigenomics in Cancer. She and her team developed a high-throughput single-cell ChIP-seq approach which relies on a droplet microfluidics platform to profile the chromatin landscape of thousands of cells. By doing so they could show that a subset of cells within untreated drug-sensitive tumors share a common chromatin signature. This would have been impossible with common bulk approaches. These cells are characterized by the loss of H3K27me3, which leads to stable transcriptional repression, influencing genes that are known to promote resistance to treatment.
In this episode we discuss how Céline Vallot had her once-in-a-lifetime scientific eureka-moment, when, during her postdoc, she first saw XACT coating the whole X-Chromosome in humans and then how she pivoted when starting her own lab and focuses now on single-cell epigenomics in cancer.
References
- Céline Vallot, Christophe Huret, … Claire Rougeulle (2013) XACT , a long noncoding transcript coating the active X chromosome in human pluripotent cells (Nature Genetics) DOI: 10.1038/ng.2530
- Kevin Grosselin, Adeline Durand, … Annabelle Gérard (2019) High-throughput single-cell ChIP-seq identifies heterogeneity of chromatin states in breast cancer (Nature Genetics) DOI: 10.1038/s41588-019-0424-9
- Pacôme Prompsy, Pia Kirchmeier, … Céline Vallot (2020) Interactive analysis of single-cell epigenomic landscapes with ChromSCape (Nature Communications) DOI: 10.1038/s41467-020-19542-x
- Justine Marsolier, Pacôme Prompsy, … Céline Vallot (2021) H3K27me3 is a determinant of chemotolerance in triple-negative breast cancer (bioRxiv) DOI: 10.1101/2021.01.04.423386
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In this episode of the Epigenetics Podcast, we caught up with Margaret (“Peggy”) Goodell from Baylor College of Medicine in Houston, Texas to talk about her work on the epigenetic regulation of stem cell self-renewal and differentiation.
Dr. Margret Goodell's laboratory focuses on how differentiation and self-renewal is regulated in hematopoietic stem cells (HSC). In the early stages of her research career, however, Dr. Goodell was able to develop a new method to purify stem cells. This method was based on the characteristic of stem cells to pump out the Hoechst dye that was used for the purification.
In recent years, the focus of the lab has been to identify how HSCs decide whether to self-renew or differentiate. To get an answer to this question, the lab has performed genome-wide screens to find differentially expressed genes during the decision process. By doing that, they recently found that the DNA methyltransferase 3A (DNMT3A) was highly and specifically expressed in HSCs and that it is required for differentiation. When DNMT3A was knocked out in HSCs, the cell population expanded dramatically and the ability to differentiate was impaired. This finding led to further experiments in this area and to the discovery of so-called DNA methylation canyons in the genome, which are large regions of very low DNA methylation that harbor highly conserved regulator genes.
In this episode we discuss how Dr. Peggy Goodell described a new approach to isolate hematopoietic stem cells even though she was not looking for that, how she discovered DNMT3A as an important factor in stem cell decision making, and how she entered and approached new fields of research along the path of her research career.
References
- M. A. Goodell, K. Brose, … R. C. Mulligan (1996) Isolation and functional properties of murine hematopoietic stem cells that are replicating in vivo (The Journal of Experimental Medicine) DOI: 10.1084/jem.183.4.1797
- Shannon McKinney-Freeman, Margaret A. Goodell (2004) Circulating hematopoietic stem cells do not efficiently home to bone marrow during homeostasis (Experimental Hematology) DOI: 10.1016/j.exphem.2004.06.010
- Stuart M. Chambers, Chad A. Shaw, … Margaret A. Goodell (2007) Aging hematopoietic stem cells decline in function and exhibit epigenetic dysregulation (PLoS biology) DOI: 10.1371/journal.pbio.0050201
- Grant A. Challen, Deqiang Sun, … Margaret A. Goodell (2011) Dnmt3a is essential for hematopoietic stem cell differentiation (Nature Genetics) DOI: 10.1038/ng.1009
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In this episode of the Epigenetics Podcast, we caught up with Dr. Keji Zhao from the National Heart, Lung, and Blood Institute at the National Institutes of Health in Bethesda, MD, to talk about his work on the genome-wide investigation of epigenetic marks and nucleosome positioning.
Dr. Keji Zhao pioneered in the development of cutting-edge techniques in the field of epigenetics. Current methods at that time relied on DNA microarrays, however, Dr. Zhao wanted a more comprehensive and unbiased approach that would avoid the shortfalls of these array-based methods. Hence, he set out to develop new sequencing-based methods like ChIP-Seq and MNase-Seq with accompanying computational methods to analyze the huge amount of sequencing data that would be generated.
Using the above-mentioned techniques, Dr. Zhao was able to show that histone deacetylases (HDACs) and histone acetyltransferases (HATs) were found at inactive and active genes, respectively, as previously thought. Surprisingly, he was also able to show that HDACs were also located at active genes. Furthermore, both, HATs and HDACs can be found at low levels at silenced genes.
In this episode we discuss the story behind how Dr. Keji Zhao was one of the pioneers of the chromatin immunoprecipitation technology, how he discovered the genomic locations of HATs and HDACs, and in the end he shares some tips and tricks on how to get the best results in ChIP-Seq assays.
References
- Artem Barski, Suresh Cuddapah, … Keji Zhao (2007) High-resolution profiling of histone methylations in the human genome (Cell) DOI: 10.1016/j.cell.2007.05.009
- Dustin E. Schones, Kairong Cui, … Keji Zhao (2008) Dynamic regulation of nucleosome positioning in the human genome (Cell) DOI: 10.1016/j.cell.2008.02.022
- Zhibin Wang, Chongzhi Zang, … Keji Zhao (2009) Genome-wide mapping of HATs and HDACs reveals distinct functions in active and inactive genes (Cell) DOI: 10.1016/j.cell.2009.06.049
- Wenfei Jin, Qingsong Tang, … Keji Zhao (2015) Genome-wide detection of DNase I hypersensitive sites in single cells and FFPE tissue samples (Nature) DOI: 10.1038/nature15740
- Binbin Lai, Weiwu Gao, … Keji Zhao (2018) Principles of nucleosome organization revealed by single-cell micrococcal nuclease sequencing (Nature) DOI: 10.1038/s41586-018-0567-3
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In this episode of the Epigenetics Podcast, we caught up with Dr. Sarah Diermeier from the University of Otago in New Zealand to talk about her work on the role of long non-coding RNAs in tumor growth and treatment.
Although only 1-2% of the human genome is transcribed into mRNAs that code for proteins, 75% of the genome is transcribed into non-coding RNAs. The function of these non-coding RNAs lie in the regulation of cellular processes and hence, offer the possibility of therapeutic intervention. Dr. Diermeier and her laboratory focus on a subset of these non-coding RNAs: the long non-coding RNAs (lncRNAs) that have been shown to play a role in breast and colorectal cancers.
This interview discusses how the Diermeier lab uses state-of-the-art techniques to both answer fundamental questions about biological mechanisms and also for translational research approaches. We also touch upon Dr. Diermeier becoming mother during her first years being a PI and the challenges and opportunities faced while raising a child and running a lab, and how the University of Otago and the State of New Zealand support young mothers in science.
This episode also tells the stories behind how Dr. Sarah Diermeier ended up in New Zealand, how her childhood influenced her career path, the role of lncRNAs in cancer, and how she deals with being a young PI and a mother at the same time.
References
- R. Gualdi, P. Bossard, … K. S. Zaret (1996) Hepatic specification of the gut endoderm in vitro: cell signaling and transcriptional control (Genes & Development) DOI: 10.1101/gad.10.13.1670
- L. A. Cirillo, C. E. McPherson, … K. S. Zaret (1998) Binding of the winged-helix transcription factor HNF3 to a linker histone site on the nucleosome (The EMBO journal) DOI: 10.1093/emboj/17.1.244
- Lisa Ann Cirillo, Frank Robert Lin, … Kenneth S. Zaret (2002) Opening of compacted chromatin by early developmental transcription factors HNF3 (FoxA) and GATA-4 (Molecular Cell) DOI: 10.1016/s1097-2765(02)00459-8
Related Episodes
- Chromatin Structure and Dynamics at Ribosomal RNA Genes (Tom Moss)
- The Role of Small RNAs in Transgenerational Inheritance in C. elegans (Oded Rechavi)
- Influence of Dynamic RNA Methylation on Gene Expression (Chuan He)
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In this episode of the Epigenetics Podcast, we caught up with Job Dekker from the University of Massachusetts Medical School to talk about his work on unraveling mechanisms of chromosome formation.
In 2002, during graduate school, Job Dekker was the first author on the paper describing the chromosome conformation capture (3C) method, which revolutionized the field of nuclear architecture. In the 3C protocol, chromatin is crosslinked using formaldehyde and then digested using a restriction enzyme. After ligating the digested blunt ends of crosslinked DNA fragments together they can be analyzed using qPCR. In the next couple of years 3C was further developed and methods like 4C, 5C, and Hi-C were published. This led to the generation of genome-wide contact maps which helped understand the 3-D organization of the nucleus.
Job Dekker’s research group is also part of the 4D Nucleome initiative, which is dedicated to understanding the structure of the human genome. More recent work of the lab includes analyzing interactions between and along sister chromatids with a method called SisterC and expanding their research to organisms like dinoflagellates to learn more about the basic organization principles of the genome.
In this episode, we discuss the story behind the idea of the chromosome conformation capture method, how close Job Dekker was to giving up on it, how the 3C methods evolved, the importance of data visualization, and we touch on parts of his current work on dinoflagellates.
References
- Job Dekker, Karsten Rippe, … Nancy Kleckner (2002) Capturing Chromosome Conformation (Science) DOI: 10.1126/science.1067799
- Josée Dostie, Todd A. Richmond, … Job Dekker (2006) Chromosome Conformation Capture Carbon Copy (5C): A massively parallel solution for mapping interactions between genomic elements (Genome Research) DOI: 10.1101/gr.5571506
- Erez Lieberman-Aiden, Nynke L. van Berkum, … Job Dekker (2009) Comprehensive Mapping of Long-Range Interactions Reveals Folding Principles of the Human Genome (Science) DOI: 10.1126/science.1181369
- Amartya Sanyal, Bryan R. Lajoie, … Job Dekker (2012) The long-range interaction landscape of gene promoters (Nature) DOI: 10.1038/nature11279
- Marlies E. Oomen, Adam K. Hedger, … Job Dekker (2020) Detecting chromatin interactions between and along sister chromatids with SisterC (Nature Methods) DOI: 10.1038/s41592-020-0930-9 • Job Dekker, Andrew S. Belmont, … 4D Nucleome Network (2017) The 4D nucleome project (Nature) DOI: 10.1038/nature23884 • The 4D Nucleome Project
Related Episodes
- Hi-C and Three-Dimensional Genome Sequencing (Erez Lieberman Aiden)
- Identification of Functional Elements in the Genome (Bing Ren)
- Biophysical Modeling of 3-D Genome Organization (Leonid Mirny)
- Epigenetics and X-Inactivation (Edith Heard)
- Dosage Compensation in Drosophila (Asifa Akhtar)
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In this episode of the Epigenetics Podcast, we caught up with Dr. Danny Reinberg from the New York University School of Medicine to talk about his work on transcription and polycomb in inheritance and disease.
Dr. Danny Reinberg is a pioneer in the characterization of transcription factors for human RNA polymerase II. In his groundbreaking work in the 1990s, he purified the essential transcription factors and reconstituted the polymerase in vitro on both naked DNA and chromatin. Dr. Reinberg next started focusing on the polycomb repressive complex 2 (PRC2), which is the only known methyltransferase for lysine 27 on histone H3. He biochemically characterized the PRC2 subunits EZH1 and EZH2. More recently, Dr. Reinberg has been investigating the role of PRC2 in neurons.
This interview discusses the story behind how Dr. Danny Reinberg started his research career by identifying the essential RNA polymerase transcription factors, how he discovered and characterized the polycomb repressive complex 2 (PRC2), and what his research holds for the future.
References
- H. Lu, L. Zawel, … D. Reinberg (1992) Human general transcription factor IIH phosphorylates the C-terminal domain of RNA polymerase II (Nature) DOI: 10.1038/358641a0
- A. Merino, K. R. Madden, … D. Reinberg (1993) DNA topoisomerase I is involved in both repression and activation of transcription (Nature) DOI: 10.1038/365227a0
- G. Orphanides, W. H. Wu, … D. Reinberg (1999) The chromatin-specific transcription elongation factor FACT comprises human SPT16 and SSRP1 proteins (Nature) DOI: 10.1038/22350
- Andrei Kuzmichev, Kenichi Nishioka, … Danny Reinberg (2002) Histone methyltransferase activity associated with a human multiprotein complex containing the Enhancer of Zeste protein (Genes & Development) DOI: 10.1101/gad.1035902
- Andrei Kuzmichev, Raphael Margueron, … Danny Reinberg (2005) Composition and histone substrates of polycomb repressive group complexes change during cellular differentiation (Proceedings of the National Academy of Sciences of the United States of America) DOI: 10.1073/pnas.0409875102
- Ozgur Oksuz, Varun Narendra, … Danny Reinberg (2018) Capturing the Onset of PRC2-Mediated Repressive Domain Formation (Molecular Cell) DOI: 10.1016/j.molcel.2018.05.023
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In this episode of the Epigenetics Podcast, we caught up with Dr. Sandra Atlante and Dr. Carlo Gaetano from the Instituti Clinici Scientifici Maugeri in Pavia, Italy, to talk about the roles epigenetic mechanisms play in COVID-19.
In early 2020 a novel coronavirus, SARS-CoV-2, emerged in Wuhan, China. This coronavirus causes the coronavirus disease 2019 (COVID-19) and rapidly spread all over the globe. In a worldwide effort, scientists and doctors tried to find drugs and looked for vaccines to help contain the spreading of the virus. It seems that an overreaction of the immune system, the so called "cytokine storm," could be one of the major complications of this disease. This reaction is not directly linked to the viral infection but is an overreaction of the body's own immune system. Therefore, small molecules that regulate gene expression via chromatin modifying enzymes might help keep the immune system in check.
In this episode we discuss how Dr. Gaetano and Dr. Atlante set up studies to investigate the epigenetic response to a SARS-CoV-2 infection, which epigenetic factors play a role in disease progression, and what we can expect from mutations of the virus in the future.
References
- Sandra Atlante, Alessia Mongelli, … Carlo Gaetano (2020) The epigenetic implication in coronavirus infection and therapy (Clinical Epigenetics) DOI: 10.1186/s13148-020-00946-x
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In this episode of the Epigenetics Podcast, we caught up with Dr. Wolf Reik, Director at the Babraham Institute in Cambridge, UK, to talk about his work on the role of epigenetic factors in cellular reprogramming.
In the beginning of his research career, Dr. Wolf Reik worked on cellular reprogramming during embryogenesis. Epigenetic marks like DNA methylation or post-translational modifications of histone tails are removed and reprogrammed during embryogenesis, which can limit the amount of epigenetic information that can be passed on to future generations. However, this process is sometimes defective, which can lead to transgenerational epigenetic inheritance.
More recently, the laboratory of Dr. Wolf Reik has done pioneering work in the emerging field of single-cell experimental methods. The Reik lab developed a single-cell reduced representation bisulfite sequencing (scRRBS) approach to investigate DNA methylation at single-cell resolution. They also developed an integrated multi-omics approach called single-cell nucleosome, methylation, and transcription sequencing (scNMT-Seq) to map chromatin accessibility, DNA methylation, and RNA expression at the same time during the onset of gastrulation in mouse embryos.
In this interview, we discuss the story behind how Dr. Wolf Reik almost discovered 5-hmC and how he later moved into developing single-cell methods like scRRBS and single-cell multi-omics approaches.
References
- W. Reik, A. Collick, … M. A. Surani (1987) Genomic imprinting determines methylation of parental alleles in transgenic mice (Nature) DOI: 10.1038/328248a0
- W. Dean, F. Santos, … W. Reik (2001) Conservation of methylation reprogramming in mammalian development: aberrant reprogramming in cloned embryos (Proceedings of the National Academy of Sciences of the United States of America) DOI: 10.1073/pnas.241522698
- Miguel Constância, Myriam Hemberger, … Wolf Reik (2002) Placental-specific IGF-II is a major modulator of placental and fetal growth (Nature) DOI: 10.1038/nature00819
- Adele Murrell, Sarah Heeson, Wolf Reik (2004) Interaction between differentially methylated regions partitions the imprinted genes Igf2 and H19 into parent-specific chromatin loops (Nature Genetics) DOI: 10.1038/ng1402
- Irene Hernando-Herraez, Brendan Evano, … Wolf Reik (2019) Ageing affects DNA methylation drift and transcriptional cell-to-cell variability in mouse muscle stem cells (Nature Communications) DOI: 10.1038/s41467-019-12293-4
- Tobias Messmer, Ferdinand von Meyenn, … Wolf Reik (2019) Transcriptional Heterogeneity in Naive and Primed Human Pluripotent Stem Cells at Single-Cell Resolution (Cell Reports) DOI: 10.1016/j.celrep.2018.12.099
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In this episode of the Epigenetics Podcast, we caught up with Dr. Srinivas Ramachandran, Assistant Professor at the University of Colorado, Anschutz Medical Campus, to talk about his work on in vivo nucleosome structure and dynamics.
Dr. Srinivas Ramachandran studies the structure and dynamics of nucleosomes during cellular processes like transcription and DNA replication. During transcription, as the RNA polymerase transcribes along the DNA, it needs to pass nucleosomes. Dr. Ramachandran investigated the effect of nucleosomes on transcription and also studied how different histone variants affect this process. He found that the first nucleosome within a gene body is a barrier for the progression of RNA polymerase, and that presence of the histone variant H2A.Z in this first nucleosome lowers this barrier.
Furthermore, Dr. Ramachandran developed a method called mapping in vivo nascent chromatin using EdU and sequencing (MINCE-Seq), enabling the study of chromatin landscapes right after DNA replication. In MINCE-Seq, newly replicated DNA is labeled right after the replication fork has passed by with the nucleotide analog ethynyl deoxyuridine (EdU), which can then be coupled with biotin using click chemistry. After the purification of newly replicated DNA and MNase digestion, the chromatin landscape can be analyzed.
In this interview, we discuss the story behind how Dr. Ramachandran found his way into chromatin research, what it was like to start a wet lab postdoc with a bioinformatics background, and what he is working on now to unravel nucleosomal structure and dynamics in his own lab.
References
- Christopher M. Weber, Srinivas Ramachandran, Steven Henikoff (2014) Nucleosomes are context-specific, H2A.Z-modulated barriers to RNA polymerase (Molecular Cell) DOI: 10.1016/j.molcel.2014.02.014
- Srinivas Ramachandran, Steven Henikoff (2016) Transcriptional Regulators Compete with Nucleosomes Post-replication (Cell) DOI: 10.1016/j.cell.2016.02.062
- Srinivas Ramachandran, Kami Ahmad, Steven Henikoff (2017) Transcription and Remodeling Produce Asymmetrically Unwrapped Nucleosomal Intermediates (Molecular Cell) DOI: 10.1016/j.molcel.2017.11.015
- Satyanarayan Rao, Kami Ahmad, Srinivas Ramachandran (2020) Cooperative Binding of Transcription Factors is a Hallmark of Active Enhancers (bioRxiv) DOI: 10.1101/2020.08.17.253146
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In this episode of the Epigenetics Podcast, we caught up with Dr. Ken Zaret, Professor in the Department of Cell and Developmental Biology at the Perelman School of Medicine, University of Pennsylvania, to talk about his work on pioneer transcription factors and their influence on chromatin structure.
Embryonic development is a complex process that needs to be tightly regulated. Multiple regulatory factors contribute to proper development, including a family of specialized regulatory proteins called "pioneer factors." Our guest Dr. Ken Zaret found that these pioneer factors are among the first proteins to bind to chromatin during development and that they can prime important regulatory genes for activation at a later developmental stage. Furthermore, he and his team showed that there might be a "pre-pattern" that exists in cells that determines their developmental fate.
Pioneer factors are not only important in embryonic development, they can also help restart transcription after mitosis. Dr. Zaret and his colleagues demonstrated that FoxA stays bound to chromosomes during mitosis, leading to a rapid reactivation of essential genes at the exit of mitosis.
In this interview, we discuss the story behind how Dr. Zaret discovered pioneer transcription factors like FoxA, how these factors are influenced by the chromatin environment, and how they function.
References
- R. Gualdi, P. Bossard, … K. S. Zaret (1996) Hepatic specification of the gut endoderm in vitro: cell signaling and transcriptional control (Genes & Development) DOI: 10.1101/gad.10.13.1670
- L. A. Cirillo, C. E. McPherson, … K. S. Zaret (1998) Binding of the winged-helix transcription factor HNF3 to a linker histone site on the nucleosome (The EMBO journal) DOI: 10.1093/emboj/17.1.244
- Lisa Ann Cirillo, Frank Robert Lin, … Kenneth S. Zaret (2002) Opening of compacted chromatin by early developmental transcription factors HNF3 (FoxA) and GATA-4 (Molecular Cell) DOI: 10.1016/s1097-2765(02)00459-8
- Kenneth S. Zaret (2020) Pioneer Transcription Factors Initiating Gene Network Changes (Annual Review of Genetics) DOI: 10.1146/annurev-genet-030220-015007
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In this episode of the Epigenetics Podcast, we caught up with Dr. Oded Rechavi, Professor at the University of Tel Aviv, to talk about his work on the role of small RNAs in transgenerational inheritance in C. elegans.
The most prominent example of transgenerational inheritance is the Dutch famine of 1944 during World War II. Effects of this famine could be observed in the grandchildren of people that lived through this hunger winter, but the molecular mechanisms involved remain largely unknown. The guest of this podcast episode, Dr. Rechavi, has taken on the challenge to unravel parts of this puzzle by studying transgenerational epigenetics in C. elegans.
It was already known that small RNA molecules could play a role in passing on information from one generation to the next, but it was not clear what exactly was being inherited. Was it RNAs? Or chromatin modifications? Or something else?
Dr. Rechavi made several important discoveries in his journey to answer these questions. He started out by showing that RNAi provides an antiviral protection mechanism in C. elegans that can be passed on over multiple generations. He then went on to show that starvation in one generation leads to changes in the lifespan of future generations, and investigate how long this memory could last. Simple dilution of the parental RNA in future generations could not be the answer because the inherited phenotypes lasted much longer than would be possible if this were the case. This led Dr. Rechavi to the discovery that small RNAs were amplified in each generation, and the effect of a stimulus could affect multiple generations. More recently, Dr. Rechavi and his team studied the interplay of neurons and the germ line and how information can be passed on from the brain to the germ line.
In this interview, we cover how Dr. Rechavi chose C. elegans as a model organism, discuss his first major discoveries in the field of transgenerational effects of starvation, and what role epigenetic factors play in this process.
References
- Oded Rechavi, Gregory Minevich, Oliver Hobert (2011) Transgenerational Inheritance of an Acquired Small RNA-Based Antiviral Response in C. elegans (Cell) DOI: 10.1016/j.cell.2011.10.042
- Oded Rechavi, Leah Houri-Ze’evi, … Oliver Hobert (2014) Starvation-induced transgenerational inheritance of small RNAs in C. elegans (Cell) DOI: 10.1016/j.cell.2014.06.020
- Leah Houri-Ze’evi, Yael Korem, … Oded Rechavi (2016) A Tunable Mechanism Determines the Duration of the Transgenerational Small RNA Inheritance in C. elegans (Cell) DOI: 10.1016/j.cell.2016.02.057
- Itamar Lev, Uri Seroussi, … Oded Rechavi (2017) MET-2-Dependent H3K9 Methylation Suppresses Transgenerational Small RNA Inheritance (Current biology: CB) DOI: 10.1016/j.cub.2017.03.008
- Leah Houri-Zeevi, Yael Korem Kohanim, … Oded Rechavi (2020) Three Rules Explain Transgenerational Small RNA Inheritance in C. elegans (Cell) DOI: 10.1016/j.cell.2020.07.022
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In this episode of the Epigenetics Podcast, we caught up with Dr. Hodaka Fujii, Professor of Biochemistry and Genome Biology at Hirosaki University Graduate School of Medicine and School of Medicine, to talk about his work on the development of locus-specific ChIP technologies.
The goal of conventional chromatin immunoprecipitation (ChIP) assays is to find genomic locations of transcription factor binding or genome-wide profiles of histone tail modifications. In contrast to that, the guest of this episode, Dr. Fujii, has developed methods such as insertional chromatin immunoprecipitation (iChIP) and engineered DNA-binding molecule-mediated chromatin immunoprecipitation (enChIP) to identify the factors that are binding to specific sites on the genome.
In iChIP, LexA binding sites are inserted into the genomic region of interest. In parallel, the DNA-binding domain of LexA, fused with FLAG epitope tags and a nuclear localization signal, is expressed in the same cells. After crosslinking and chromatin preparation, the resulting chromatin is immunoprecipitated with an antibody against the tag. This allows proteins or RNA interacting with the region of interest to be analyzed with the appropriate downstream application. The enChIP takes a similar approach, but does not require insertion of the LexA binding sites. Instead, a FLAG-tagged dCas9 protein together with the respective guide RNA are used to target the region of the genome of interest. After the IP and the purification DNA, RNA, or proteins can be analyzed accordingly. The lack of the requirement of to insert the LexA binding sites into the genome makes enChIP much more straightforward than iChIP.
In this interview, we discuss the story behind how Dr. Fujii got into the field of epigenetics, how he developed iChIP, and how the method was improved over the years. Furthermore, we discuss the development of enChIP and how this can be used as an alternate method to Hi-C.
References
- Akemi Hoshino, Satoko Matsumura, … Hodaka Fujii (2004) Inducible Translocation Trap (Molecular Cell) DOI: 10.1016/j.molcel.2004.06.017
- Akemi Hoshino, Hodaka Fujii (2009) Insertional chromatin immunoprecipitation: a method for isolating specific genomic regions (Journal of Bioscience and Bioengineering) DOI: 10.1016/j.jbiosc.2009.05.005
- Toshitsugu Fujita, Hodaka Fujii (2013) Efficient isolation of specific genomic regions and identification of associated proteins by engineered DNA-binding molecule-mediated chromatin immunoprecipitation (enChIP) using CRISPR (Biochemical and Biophysical Research Communications) DOI: 10.1016/j.bbrc.2013.08.013
- Toshitsugu Fujita, Miyuki Yuno, … Hodaka Fujii (2015) Identification of Non-Coding RNAs Associated with Telomeres Using a Combination of enChIP and RNA Sequencing (PLOS ONE) DOI: 10.1371/journal.pone.0123387
- Toshitsugu Fujita, Miyuki Yuno, Hodaka Fujii (2016) Efficient sequence-specific isolation of DNA fragments and chromatin by in vitro enChIP technology using recombinant CRISPR ribonucleoproteins (Genes to Cells) DOI: 10.1111/gtc.12341
- Toshitsugu Fujita, Miyuki Yuno, … Hodaka Fujii (2017) Identification of physical interactions between genomic regions by enChIP-Seq (Genes to Cells) DOI: 10.1111/gtc.12492
- Toshitsugu Fujita, Fusako Kitaura, … Hodaka Fujii (2017) Locus-specific ChIP combined with NGS analysis reveals genomic regulatory regions that physically interact with the Pax5 promoter in a chicken B cell line (DNA Research) DOI: 10.1093/dnares/dsx023
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In this episode of the Epigenetics Podcast, we caught up with Geneviève Almouzni, Ph.D., Research Director at the CNRS at Institut Curie in Paris, to talk about her work on the regulation of chromatin organization by histone chaperones.
Geneviève Almouzni got her Ph.D. from Université Pierre-et-Marie-Curie in 1988 under the supervision of Marcel Méchali. She then moved to the United States to work as a postdoc in the National Institutes of Health in the laboratory of Professor Alan Wolffe. In 1994, she returned to Paris and became a Junior Group Leader at Institut Curie and became a Group Leader there in 2000. In 2013, she took over the direction of research at the Institut Curie and became the third woman to hold this position, after Marie Curie and Irène Joliot-Curie.
Geneviève Almouzni’s research focuses on the assembly of chromatin and the identification of histone chaperones. Histone chaperones are necessary for the establishment and maintenance of chromatin, as they help to assemble the nucleosomes out of the core histones and DNA. This occurs both when the polymerase transcribes through a nucleosome and after DNA replication and repair.
The Almouzni group has identified and characterized multiple histone chaperones, including CAF-1, HirA, and HJURP. Furthermore, they investigated how post-translational modifications on soluble histones influence the final epigenetic state of the nucleosome and the reassembly of chromatin after DNA replication. In the last couple of years, the group has focused on the unraveling the link between the structure of chromatin at centromeres and cancer.
In this interview, we discuss the focus of the Almouzni lab on histone chaperones, how the lab was able to identify its first one with CAF-1, how histone PTMs on soluble histones influence the deposition on the DNA, and how the chromatin on centromeres is involved in cancer.
References
- Dominique Ray-Gallet, Jean-Pierre Quivy, … Geneviève Almouzni (2002) HIRA Is Critical for a Nucleosome Assembly Pathway Independent of DNA Synthesis (Molecular Cell) DOI: 10.1016/S1097-2765(02)00526-9
- Pierre-Henri L. Gaillard, Emmanuelle M.-D. Martini, … Geneviève Almouzni (1996) Chromatin Assembly Coupled to DNA Repair: A New Role for Chromatin Assembly Factor I (Cell) DOI: 10.1016/S0092-8674(00)80164-6
- Jean-Pierre Quivy, Danièle Roche, … Geneviève Almouzni (2004) A CAF-1 dependent pool of HP1 during heterochromatin duplication (The EMBO Journal) DOI: 10.1038/sj.emboj.7600362
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In this episode of the Epigenetics Podcast, we caught up with Dr. Christine Cucinotta and Dr. Melvin Noe Gonzalez to talk about how they brought the #fragilenucleosome seminar series and Discord channel to life.
Christine Cucinotta and Melvin Noe Gonzales are part of the organizing committee of the independent scientific community "Fragile Nucleosome." This community consists of a Discord channel with more than 1,000 members, a biweekly seminar series, a mentoring program, and a journal club series. The Fragile Nucleosome is organized exclusively by early-career scientists, without external sponsors or under the roof of a single graduate program or university.
In this interview, Christine and Melvin share the story on how the Fragile Nucleosome community got started, what has happened so far, and what the future plans are for the #fragilenucleosome.
References
-
fragilenucleosome on Twitter
- Fragile Nucleosome Discord Channel
- Fragile Nucleosome on generegulation.org
- Christine Cucinotta on Twitter
- Melvin Noe Gonzalez on Twitter
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In this episode of the Epigenetics Podcast, we caught up with Professor Isabelle Mansuy, Ph.D., from the University of Zürich and the ETH Zürich, to talk about her work on epigenetic influences on memory formation and inheritance.
Dr. Mansuy received her Ph.D. from the Friedrich Miescher Institute, Basel, Switzerland in 1994. After doing a postdoc at the Center for Neurobiology and Behavior at the Howard Hughes Medical Institute at the Columbia University in New York, she moved to Zürich and became Assistant Professor in Neurobiology at the Department of Biology at the Swiss Federal Institute of Technology in 1998. In 2004 Dr. Mansuy became Professor at the Brain Research Institute of the University Zurich, where, in 2007, she became Managing Director. Since 2013 she has been a full Professor in Neuroepigenetics at the University of Zürich and at the ETH in Zürich.
Dr. Isabelle Mansuy's work centers around the formation of memories and how those memories are inherited. She started to work on memory formation in the beginning of her research career, where she investigated the influence of calcineurin and Zif268 in this process. In the early 2010s she pivoted and transitioned to work on transgenerational epigenetic inheritance. To investigate this field of research she created an unbiased experiment that allowed her to study the transgenerational influence of early life stress, which she was able to observe for across up to 4 generations through the germline.
If you want to learn more about the challenges and obstacles that needed to be overcome to create this novel experimental approach to tackle the questions of and which epigenetic factors might influence transgenerational epigenetic inheritance, don't miss out on this episode.
References
- Karsten Baumgärtel, David Genoux, … Isabelle M. Mansuy (2008) Control of the establishment of aversive memory by calcineurin and Zif268 (Nature Neuroscience) DOI: 10.1038/nn.2113
- Tamara B. Franklin, Holger Russig, … Isabelle M. Mansuy (2010) Epigenetic Transmission of the Impact of Early Stress Across Generations (Biological Psychiatry) DOI: 10.1016/j.biopsych.2010.05.036
- Johannes Gräff, Bisrat T. Woldemichael, … Isabelle M. Mansuy (2012) Dynamic histone marks in the hippocampus and cortex facilitate memory consolidation (Nature Communications) DOI: 10.1038/ncomms1997
- Eloïse A. Kremer, Niharika Gaur, … Isabelle M. Mansuy (2018) Interplay between TETs and microRNAs in the adult brain for memory formation (Scientific Reports) DOI: 10.1038/s41598-018-19806-z
- Katharina Gapp, Ali Jawaid, … Isabelle M. Mansuy (2014) Implication of sperm RNAs in transgenerational inheritance of the effects of early trauma in mice (Nature Neuroscience) DOI: 10.1038/nn.3695
- Katharina Gapp, Saray Soldado-Magraner, … Isabelle M. Mansuy (2014) Early life stress in fathers improves behavioural flexibility in their offspring (Nature Communications) DOI: 10.1038/ncomms6466
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In this episode of the Epigenetics Podcast, we caught up with Dr. Chuan He, John T. Wilson Distinguished Service Professor at University of Chicago, to talk about his work on the influence of dynamic RNA methylation on gene expression. RNA methylation is an important biological process, and cellular RNA methylation levels can have profound impacts on normal cellular differentiation and cancer cell proliferation.
Dr. He received his Ph.D. from MIT in 2000 and went on to do his postdoctoral work at Harvard University. He then became Assistant Professor at the University of Chicago in 2002, was promoted to Associate Professor in 2008, and in 2014 he became the John T. Wilson Distinguished Service Professor at the University of Chicago. From 2012 to 2017 he was Director of the Institute for Biophysical Dynamics at the University of Chicago.
Chuan He's current research focuses on understanding the reversible RNA modification m6A. This modification was discovered in the 1980s, but work from Dr. He's laboratory showing that m6A was indeed a transient epigenetic modification by the discovery of the first m6A demethylase FTO in 2011 rekindled the interest in this modification. In the following years Dr. He and his team identified and characterized additional m6A enzymes, including the m6A eraser ALKBH5, the m6A readers YTH and HNRNP, and the m6A writer complex METTL3/14.
METTL3/14 is a core complex in this regulatory network, and it requires an accessory factor WTAP, which mediates cellular m6A RNA methylation. The current work in the He lab focuses on how the methylation selectivity of this complex is achieved.
In this interview, we discuss the story of how the He lab discovered the members of the family of proteins that read, write, and erase RNA modifications and how those RNA modifications act in the field of epigenetics.
References
- Guifang Jia, Cai-Guang Yang, … Chuan He (2008) Oxidative demethylation of 3-methylthymine and 3-methyluracil in single-stranded DNA and RNA by mouse and human FTO (FEBS letters) DOI: 10.1016/j.febslet.2008.08.019
- Guifang Jia, Ye Fu, … Chuan He (2011) N6-methyladenosine in nuclear RNA is a major substrate of the obesity-associated FTO (Nature Chemical Biology) DOI: 10.1038/nchembio.687
- Guanqun Zheng, John Arne Dahl, … Chuan He (2013) ALKBH5 is a mammalian RNA demethylase that impacts RNA metabolism and mouse fertility (Molecular Cell) DOI: 10.1016/j.molcel.2012.10.015
- Jianzhao Liu, Yanan Yue, … Chuan He (2014) A METTL3-METTL14 complex mediates mammalian nuclear RNA N6-adenosine methylation (Nature Chemical Biology) DOI: 10.1038/nchembio.1432
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In this episode of the Epigenetics Podcast, we caught up with Dr. Michelle Trenkmann, Senior Editor at Nature. We discussed her work as an editor at Nature and how she contributed to the ENCODE 3 publications, which are the results of the third phase of the ENCODE project. Dr. Trenkmann also talked about how to get your research published in Nature and what it’s like to review high profile scientific articles.
ENCODE References
- Immersive ENCODE Website
- Perspectives on ENCODE
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In this episode of the Epigenetics Podcast, we caught up with Professor Bill Earnshaw, Wellcome Trust Principal Research Fellow at the University of Edinburgh, to talk about his work on the role of non-histone proteins in chromosome structure and function during mitosis.
In the beginning of Bill Earnshaw's research career little was known about the structure that holds the two individual sister chromatids together. This led to Bill pioneering in the use of autoantibodies for the identification and cloning of key chromosomal proteins. He used serum from a scleroderma patient to identify and clone human centromeric proteins, which paved the way for the molecular characterization of the metazoan kinetochore.
Later the chromosomal passenger complex (CPC) was identifies in his lab using biochemical studies. This complex contains Aurora B kinase plus its targeting and regulatory subunits INCENP, Survivin, and Borealin/Dasra B.
More recently, he teamed up with the laboratories of Job Dekker and Leonid Mirny. In this collaboration they used a system for synchronous mitotic entry developed by Kumiko Samejima.These studies used a combination of chemical biology, gene targeting, Hi-C genomics, and polymer modeling to explore the roles of condensin I and condensin II in mitotic chromosome formation. The results revealed that during prophase interphase higher-order chromatin organization breaks down and subsequently condensin II and condensin I work together to form hierarchical loops that give chromosomes their compact morphology.
In this interview, we discuss the story on how centromeric proteins were first identified using sera from human scleroderma patients, how the chromosomal passenger complex was discovered, and how condensin I and II work together in chromatin loop formation.
References
- Johan H. Gibcus, Kumiko Samejima, … Job Dekker (2018) A pathway for mitotic chromosome formation (Science (New York, N.Y.)) DOI: 10.1126/science.aao6135
- A. F. Pluta, A. M. Mackay, … W. C. Earnshaw (1995) The Centromere: Hub of Chromosomal Activities (Science) DOI: 10.1126/science.270.5242.1591
- Nuno M. C. Martins, Jan H. Bergmann, … William C. Earnshaw (2016) Epigenetic engineering shows that a human centromere resists silencing mediated by H3K27me3/K9me3 (Molecular Biology of the Cell) DOI: 10.1091/mbc.E15-08-0605
- Oscar Molina, Giulia Vargiu, … William C. Earnshaw (2016) Epigenetic engineering reveals a balance between histone modifications and transcription in kinetochore maintenance (Nature Communications) DOI: 10.1038/ncomms13334
- Jan G Ruppert, Kumiko Samejima, … William C Earnshaw (2018) HP 1α targets the chromosomal passenger complex for activation at heterochromatin before mitotic entry (The EMBO Journal) DOI: 10.15252/embj.201797677
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In this episode of the Epigenetics Podcast, we caught up with Dr. Dirk Schübeler, Director of the Friedrich Miescher Institute (FMI) in Basel, Switzerland, to talk about his work on the effects of DNA methylation on chromatin structure and transcription.
Dirk Schübeler was born in Germany and started his scientific career in Braunschweig, Germany. After his postdoc at the Fred Hutchinson Cancer Research Center in Seattle, he joined the FMI in 2003 and never left. He was recently appointed as the Director of the FMI in March 2020.
Dirk Schübeler’s research focuses on DNA methylation and its effects on chromatin and transcription. It is widely known that DNA methylation leads to gene silencing, but many of the mechanisms and regulatory factors involved in this process remain understudied. Therefore, Dirk Schübeler and his team set out to characterize the DNA methylation profiles in normal human somatic cells and compare them with the methylation profiles in transformed human cells. More recent work in his lab led by postdoc Tuncay Baubec focused on factors that bind to methylated DNA regions and modify chromatin structure. The factors they studied include the MBD protein family and also proteins like DNMT3B.
In this interview, we discuss the impact of DNA methylation on chromatin states, how CpG-binding factors influence those processes, and we also talk about his new role as Director of the Friedrich Miescher Institute.
References
- Tuncay Baubec, Daniele F. Colombo, … Dirk Schübeler (2015) Genomic profiling of DNA methyltransferases reveals a role for DNMT3B in genic methylation (Nature) DOI: 10.1038/nature14176
- Paul Adrian Ginno, Lukas Burger, … Dirk Schübeler (2018) Cell cycle-resolved chromatin proteomics reveals the extent of mitotic preservation of the genomic regulatory landscape (Nature Communications) DOI: 10.1038/s41467-018-06007-5
- Michael B. Stadler, Rabih Murr, … Dirk Schübeler (2011) DNA-binding factors shape the mouse methylome at distal regulatory regions (Nature) DOI: 10.1038/nature10716
- Silvia Domcke, Anaïs Flore Bardet, … Dirk Schübeler (2015) Competition between DNA methylation and transcription factors determines binding of NRF1 (Nature) DOI: 10.1038/nature16462
- Florian Lienert, Christiane Wirbelauer, … Dirk Schübeler (2011) Identification of genetic elements that autonomously determine DNA methylation states (Nature Genetics) DOI: 10.1038/ng.946
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In this episode of the Epigenetics Podcast, we caught up with Sir Adrian Bird, Buchanan Professor of Genetics at the University of Edinburgh to talk about his work on CpG islands, DNA methylation, and the role of DNA methylation in human diseases.
Adrian Bird has been a pioneer in studying the CpG dinucleotide sequence. The CpG dinucleotide is distributed genome-wide and has several properties expected of a genomic signaling module. The influence of CpG signaling on prozesses like development, differentiation, and disease is hardly understood. Adrian Bird's work indicates that proteins that bind methylated CpGs recruit chromatin modifying enzymes to promote gene silencing. On the other hand, proteins that bind unmethylated CpGs lead to the formation of active, open chromatin. These results suggest that CpGs have a gobal effect on genome activity.
In neurons MeCP2 is almost as abundant as histones and is probably one of the best studied Proteins that bind to methyl-CpGs. Children who lack MeCP2 acquire serious neurological disorders, in particular Rett Syndrome. Rett Syndrome is caused by defects of a single gene, which lead to the opportunity to study its molecular mechanism, which involves MeCP2 in detail. Adrian Bird created a mouse model of Rett Syndrome which has lead to the discovery that reintroducing a functional MeCP2 gene in mice can lead to a "curation" of the symptoms.
In this interview, podcast host Stefan Dillinger and Adrian discuss CpG islands, DNA methylation, and how the discovery of MeCP2 lead to the discovery of a possible treatment of Rett Syndrome.
References
- S. Lindsay, A. P. Bird (1987) Use of restriction enzymes to detect potential gene sequences in mammalian DNA (Nature) DOI: 10.1038/327336a0
- R. R. Meehan, J. D. Lewis, … A. P. Bird (1989) Identification of a mammalian protein that binds specifically to DNA containing methylated CpGs (Cell) DOI: 10.1016/0092-8674(89)90430-3
- R. R. Meehan, J. D. Lewis, A. P. Bird (1992) Characterization of MeCP2, a vertebrate DNA binding protein with affinity for methylated DNA (Nucleic Acids Research) DOI: 10.1093/nar/20.19.5085
- Eric U. Selker, Nikolaos A. Tountas, … Michael Freitag (2003) The methylated component of the Neurospora crassa genome (Nature) DOI: 10.1038/nature01564
- Robert J. Klose, Shireen A. Sarraf, … Adrian P. Bird (2005) DNA binding selectivity of MeCP2 due to a requirement for A/T sequences adjacent to methyl-CpG (Molecular Cell) DOI: 10.1016/j.molcel.2005.07.021
- Jacky Guy, Jian Gan, … Adrian Bird (2007) Reversal of neurological defects in a mouse model of Rett syndrome (Science (New York, N.Y.)) DOI: 10.1126/science.1138389
- Daniel H. Ebert, Harrison W. Gabel, … Michael E. Greenberg (2013) Activity-dependent phosphorylation of MeCP2 threonine 308 regulates interaction with NCoR (Nature) DOI: 10.1038/nature12348
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In this episode of the Epigenetics Podcast, we caught up with Leonid Mirny, Ph.D., from MIT to talk about his work on biophysical modeling of the 3-D structure of chromatin.
Leonid Mirny was part of the initial Hi-C paper titled "Comprehensive Mapping of Long-Range Interactions Reveals Folding Principles of the Human Genome" that was published in 2009 in the journal Science. Since then, technology has evolved and Dr. Mirny's group has developed a method called Micro-C that improves the Hi-C protocol by using MNase digestion to increase the resolution to nucleosomal level. This led to the visualization of interactions that were already predicted by his previous biophysical models.
Furthermore, Leonid Mirny worked on finding the mechanism by which chromatin loops are formed. He and his team proposed that loop extrusion underlies TAD formation. In this process, factors like cohesin and CTCF form progressively larger loops but stall at TAD boundaries due to interactions of CTCF with TAD boundaries. He used polymer simulations to show that this model produces TADs and finer-scale features of Hi-C data. Each TAD emerges from multiple loops dynamically formed through extrusion, contrary to typical illustrations of single static loops.
In this interview, we chatted with Dr. Mirny about the details of Hi-C, the development of Micro-C and how it compares to Hi-C, and how biophysical modeling helps to unravel the mechanisms behind loop extrusion.
References
- Grigory Kolesov, Zeba Wunderlich, … Leonid A. Mirny (2007) How gene order is influenced by the biophysics of transcription regulation (Proceedings of the National Academy of Sciences) DOI: 10.1073/pnas.0700672104
- Erez Lieberman-Aiden, Nynke L. van Berkum, … Job Dekker (2009) Comprehensive mapping of long-range interactions reveals folding principles of the human genome (Science (New York, N.Y.)) DOI: 10.1126/science.1181369
- Geoffrey Fudenberg, Maxim Imakaev, … Leonid A. Mirny (2016) Formation of Chromosomal Domains by Loop Extrusion (Cell Reports) DOI: 10.1016/j.celrep.2016.04.085
- Johannes Nuebler, Geoffrey Fudenberg, … Leonid A. Mirny (2018) Chromatin organization by an interplay of loop extrusion and compartmental segregation (Proceedings of the National Academy of Sciences) DOI: 10.1073/pnas.1717730115
- Martin Falk, Yana Feodorova, … Leonid A. Mirny (2019) Heterochromatin drives compartmentalization of inverted and conventional nuclei (Nature) DOI: 10.1038/s41586-019-1275-3
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In this episode of the Epigenetics Podcast, we caught up with Karolin Luger, Ph.D., from the University of Colorado in Boulder to talk about her work on solving the crystal structure of the nucleosome and on how histone chaperones like FACT act on chromatin.
During her postdoc with Timothy Richmond at the Swiss Federal Institute of Technology in Zürich, Karolin Luger was the first author on an all-time classic paper called "Crystal structure of the nucleosome core particle at 2.8 A resolution" which was published in Nature. This article was published more than 20 years ago now and it has been cited about 9000 times.
After completing her postdoc, she moved to Colorado to set up her own lab where she continued to work on the structure of the nucleosome and the factors that influence their structure. The most recent Nature paper published by her lab investigated how the FACT complex promotes both disassembly and reassembly of nucleosomes during gene transcription, DNA replication, and DNA repair.
In this interview, we discuss the efforts that went into solving the crystal structure of the nucleosome back in 1997, her work on histone chaperones, and her recent work on how FACT keeps nucleosomes intact after gene transcription.
References
- K. Luger, A. W. Mäder, … T. J. Richmond (1997) Crystal structure of the nucleosome core particle at 2.8 A resolution (Nature) DOI: 10.1038/38444
- Yang Liu, Keda Zhou, … Karolin Luger (2020) FACT caught in the act of manipulating the nucleosome (Nature) DOI: 10.1038/s41586-019-1820-0
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In this episode of the Epigenetics Podcast, we caught up with Bing Ren, Ph.D., from the University of California, San Diego and the Ludwig Institute for Cancer Research to talk about his work on identifying functional elements of the genome and higher order genome structure.
Dr. Ren’s lab invented an approach using chromatin immunoprecipitation-based methods for the identification of transcription factor binding sites and chromatin modification status genome-wide. His group was a major part of the ENCODE Project and the demonstration of this being an effective method for genome-wide mapping of cis-elements, has made their approach very popular among colleagues from the field.
His lab recently discovered Topologically associating domains (TADs), which partition the human genome into a few thousand megabase-sized domains. Interactions occur predominantly within TADs but seldom between them and are surprisingly stable during development and are evolutionarily conserved. This organisatorial pattern helps explain how enhancers, who are often located kilobases away, influence their target genes.
In this interview, we discuss the road of Bing Ren's scientific career, his role in the ENCODE Project and Roadmap Epigenome Consortia, and the discovery of Topologically associating domains (TADs).
References
- The ENCODE Project Consortium (2004) The ENCODE (ENCyclopedia Of DNA Elements) Project (Science) DOI: 10.1126/science.1105136
- Yin Shen, Feng Yue, … Bing Ren (2012) A map of the cis -regulatory sequences in the mouse genome (Nature) DOI: 10.1038/nature11243
- Tae Hoon Kim, Leah O. Barrera, … Bing Ren (2005) A high-resolution map of active promoters in the human genome (Nature) DOI: 10.1038/nature03877
- Tae Hoon Kim, Ziedulla K. Abdullaev, … Bing Ren (2007) Analysis of the Vertebrate Insulator Protein CTCF-Binding Sites in the Human Genome (Cell) DOI: 10.1016/j.cell.2006.12.048
- R. David Hawkins, Gary C. Hon, … Bing Ren (2010) Distinct Epigenomic Landscapes of Pluripotent and Lineage-Committed Human Cells (Cell Stem Cell) DOI: 10.1016/j.stem.2010.03.018
- Jesse R. Dixon, Siddarth Selvaraj, … Bing Ren (2012) Topological domains in mammalian genomes identified by analysis of chromatin interactions (Nature) DOI: 10.1038/nature11082
- Fulai Jin, Yan Li, … Bing Ren (2013) A high-resolution map of the three-dimensional chromatin interactome in human cells (Nature) DOI: 10.1038/nature12644
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In this episode of the Epigenetics Podcast, we caught up with Erez Lieberman Aiden, Ph.D. from Baylor College of Medicine and Rice University in Houston to talk about his work on developing Hi-C and investigating the three-dimensional structure of the genome. He was the first author on a publication in the journal Science titled "Comprehensive Mapping of Long-Range Interactions Reveals Folding Principles of the Human Genome" which was the paper that first introduced the Hi-C method in 2009 and he has continued studying the structure of the chromosome ever since.
Erez Lieberman Aiden is currently an Assistant Professor in both the Department of Genetics at the Baylor College of Medicine, where he directs the newly-established Center for Genome Architecture, and in the Department of Computer Science and Computational and Applied Mathematics at Rice University across the street.
In this interview, we discuss the road that Erez Lieberman Aiden went down to optimize the Hi-C protocol, the hurdles he had to overcome, and how Hi-C made it possible to probe the three-dimensional structure of the genome.
References
- Erez Lieberman-Aiden, Nynke L. van Berkum, … Job Dekker (2009) Comprehensive mapping of long-range interactions reveals folding principles of the human genome (Science (New York, N.Y.)) DOI: 10.1126/science.1181369
- Suhas S. P. Rao, Miriam H. Huntley, … Erez Lieberman Aiden (2014) A 3D Map of the Human Genome at Kilobase Resolution Reveals Principles of Chromatin Looping (Cell) DOI: 10.1016/j.cell.2014.11.021
- Adrian L. Sanborn, Suhas S. P. Rao, … Erez Lieberman Aiden (2015) Chromatin extrusion explains key features of loop and domain formation in wild-type and engineered genomes (Proceedings of the National Academy of Sciences) DOI: 10.1073/pnas.1518552112
- Suhas S.P. Rao, Su-Chen Huang, … Erez Lieberman Aiden (2017) Cohesin Loss Eliminates All Loop Domains (Cell) DOI: 10.1016/j.cell.2017.09.026
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In this episode of the Epigenetics Podcast, we caught up with Professor Tom Moss from Université Laval in Québec City, Canada to talk about his work on the chromatin structure and dynamics at ribosomal RNA genes.
Dr. Tom Moss has been a member of the Department of Molecular Biology, Medical Biochemistry, and Pathology at the Laval University School of Medicine since he was recruited from the University of Portsmouth in the United Kingdom in 1986.
Since then he focused on the ribosomal transcription factor Upstream Binding Factor (UBF) and how it regulates the chromatin structure at ribosomal RNA genes (rDNA). UBF binds to the rDNA as a dimer where it leads to six in-phase bends and induces the formation of the ribosomal enhanceosome. This enhanceosome is required for the initial step in formation of an RNA polymerase I initiation complex, and therefore plays an important role in regulating the expression of ribosomal RNA genes.
In this Interview, we discuss the function of UBF on the rDNA, how UBF impacts the chromatin landscape at rRNA genes, the role of DNA methylation in this process, and how UBF influences the structure of the nucleolus.
References
- D. Bachvarov, T. Moss (1991) The RNA polymerase I transcription factor xUBF contains 5 tandemly repeated HMG homology boxes (Nucleic Acids Research) DOI: 10.1093/nar/19.9.2331
- V. Y. Stefanovsky, D. P. Bazett-Jones, … T. Moss (1996) The DNA supercoiling architecture induced by the transcription factor xUBF requires three of its five HMG-boxes (Nucleic Acids Research) DOI: 10.1093/nar/24.16.3208
- V. Y. Stefanovsky, G. Pelletier, … T. Moss (2001) DNA looping in the RNA polymerase I enhancesome is the result of non-cooperative in-phase bending by two UBF molecules (Nucleic Acids Research) DOI: 10.1093/nar/29.15.3241
- Elaine Sanij, Jeannine Diesch, … Ross D. Hannan (2015) A novel role for the Pol I transcription factor UBTF in maintaining genome stability through the regulation of highly transcribed Pol II genes (Genome Research) DOI: 10.1101/gr.176115.114
- Tom Moss, Jean-Clement Mars, … Marianne Sabourin-Felix (2019) The chromatin landscape of the ribosomal RNA genes in mouse and human (Chromosome Research) DOI: 10.1007/s10577-018-09603-9
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In this episode of the Epigenetics Podcast, we caught up with Dr. Andrew Pospisilik from the Van Andel Institute in Grand Rapids, Michigan to talk about his work on the epigenetic origins of heterogeneity and disease.
Dr. Andrew Pospisilik worked at the Max-Planck Institute of Immunobiology and Epigenetics in Freiburg for 8 years and in 2018 he joined the Van Andel Institute as the director of its Center for Epigenetics. At the Van Andel Institute his research focuses on diabetes, neurodegenerative diseases, cancer, and obesity. The goal of the Pospisilik laboratory is to better understand epigenetic mechanisms of these diseases and the roles of epigenetics in disease susceptibility and heterogeneity.
These areas of medicine are among the most important public health challenges, with the latest estimates suggesting that they impact more than 1 billion people worldwide. Although these diverse conditions are all very different, they are now thought to be caused, at least partially, from alterations in the epigenetic mechanisms that regulate gene expression and metabolism. This interview covers recent work from the Pospisilik lab on the epigenetics of these complex diseases.
References
- https://pospisiliklab.vai.org/
- J. Andrew Pospisilik, Daniel Schramek, … Josef M. Penninger (2010) Drosophila Genome-wide Obesity Screen Reveals Hedgehog as a Determinant of Brown versus White Adipose Cell Fate (Cell) DOI: 10.1016/j.cell.2009.12.027
- Anita Öst, Adelheid Lempradl, … J. Andrew Pospisilik (2014) Paternal diet defines offspring chromatin state and intergenerational obesity (Cell) DOI: 10.1016/j.cell.2014.11.005
- Kevin Dalgaard, Kathrin Landgraf, … J. Andrew Pospisilik (2016) Trim28 Haploinsufficiency Triggers Bi-stable Epigenetic Obesity (Cell) DOI: 10.1016/j.cell.2015.12.025
- Tess Tsai-Hsiu Lu, Steffen Heyne, … J. Andrew Pospisilik (2018) The Polycomb-Dependent Epigenome Controls β Cell Dysfunction, Dedifferentiation, and Diabetes (Cell Metabolism) DOI: 10.1016/j.cmet.2018.04.013
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In this episode of the Epigenetics Podcast, we caught up with Karol Bomsztyk M.D. and Tom Matula, Ph.D. from the University of Washington and Matchstick Technologies, to talk about their work on DNA and chromatin sonication.
During his career, Karol's research has focused on improving ChIP protocols to make them faster, easier and higher throughput. First, to make ChIP assays faster, Karol and his lab developed "Fast-ChIP". More recently, he adjusted this protocol to improve throughput and "Matrix-ChIP" was born. Tom is an expert in the field of ultrasound and cavitation and the Director of the Center for Industrial and Medical Ultrasound at the University of Washington.
To further improve and speed up the 96-well "Matrix-ChIP" protocol, Karol and Tom teamed up to found Matchstick Technologies and develop a sonication device that would be able to processes each and every well of a 96-well microplate consistently and quickly. The result of this cooperation is the PIXUL Multi-Sample Sonicator that is now available for order from Active Motif.
PIXUL is an ultrasound-based sample preparation platform that was designed completely from the ground up to provide researchers with an easy-to-use tool that is simple to set up, simple to use, and generates consistent results day in and day out. No other sample preparation platform out there can match the power and convenience of PIXUL.
PIXUL was conceived by an epigenetics researcher, and designed and built by ultrasound engineers to take the guesswork out of sample preparation. With PIXUL, sample preparation is no longer an art form, but instead a simple and predictable part of experiments that work every single time.
This interview goes into the mechanism behind sonication-based shearing of DNA and chromatin and highlights how PIXUL is different from existing sonication instruments.
References
- http://activemotif.com/PIXUL
- Karol Bomsztyk
- Tom Matula
- Innovation Imperative: New Device Speeds Disease Biomarker Search
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In this episode of the Epigenetics Podcast, we sat down with Marcus Buschbeck, Group Leader at the Josep Carreras Leukaemia Research Institute in Barcelona, to talk about his work on the histone variant macroH2A, its role in metabolism and how it contributes to the regulation of chromatin structure.
Histone variants equip chromatin with unique properties and show a specific genomic distribution. The histone variant macroH2A is unique in having a tripartite structure consisting of a N-terminal histone-fold, an intrinsically unstructured linker domain and a C-terminal macro domain. Recent discoveries show that macroH2A proteins have a major role in the nuclear organization which has the potential to explain how these proteins can act as tumor suppressors, promoters of differentiation and barriers to somatic cell reprogramming.
We discuss these topics, the mission of the Josep Carreras Leukaemia Research Institute, and much more in this episode.
References
- http://www.carrerasresearch.org/Buschbeck_Marcus
- Marcus Buschbeck, Iris Uribesalgo, … Luciano Di Croce (2009) The histone variant macroH2A is an epigenetic regulator of key developmental genes (Nature Structural & Molecular Biology) DOI: 10.1038/nsmb.1665
- Julien Douet, David Corujo, … Marcus Buschbeck (2017) MacroH2A histone variants maintain nuclear organization and heterochromatin architecture (Journal of Cell Science) DOI: 10.1242/jcs.199216
- Melanija Posavec Marjanović, Sarah Hurtado-Bagès, … Marcus Buschbeck (2017) MacroH2A1.1 regulates mitochondrial respiration by limiting nuclear NAD+ consumption (Nature Structural & Molecular Biology) DOI: 10.1038/nsmb.3481
- Oriana Lo Re, Julien Douet, … Manlio Vinciguerra (2018) Histone variant macroH2A1 rewires carbohydrate and lipid metabolism of hepatocellular carcinoma cells towards cancer stem cells (Epigenetics) DOI: 10.1080/15592294.2018.1514239
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In this Episode we sat down with Shelley Berger, Keynote Speaker at the "EMBO | EMBL Symposium: Metabolism Meets Epigenetics" to talk about her work on Epigenetic Mechanisms of Aging and Longevity. On how cytoplasmic chromatin fragments are involved in these processes, how alcohol has an effect on Histone PTMs in the brain and last but not least how Ants became her favorite Model Organism.
References
- Hazel A. Cruickshanks, Tony McBryan, … Peter D. Adams (2013) Senescent cells harbour features of the cancer epigenome (Nature Cell Biology) DOI: 10.1038/ncb2879
- Zhixun Dou, Kanad Ghosh, … Shelley L. Berger (2017) Cytoplasmic chromatin triggers inflammation in senescence and cancer (Nature) DOI: 10.1038/nature24050
- Hua Yan, Comzit Opachaloemphan, … Claude Desplan (2017) An Engineered orco Mutation Produces Aberrant Social Behavior and Defective Neural Development in Ants (Cell) DOI: 10.1016/j.cell.2017.06.051
- P. Mews, G. Egervari, … S. L. Berger (2019) Alcohol metabolism contributes to brain histone acetylation (Nature) DOI: 10.1038/s41586-019-1700-7
- Karl M. Glastad, Riley J. Graham, … Shelley L. Berger (2019) Epigenetic Regulator CoREST Controls Social Behavior in Ants (Molecular Cell) DOI: 10.1016/j.molcel.2019.10.012
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In this Episode of the Epigenetics Podcast our guest Lucy Stead from the University of Leeds provides insight into her work on intratumor heterogeneity in Glioblastoma. In order to tackle this area she uses an holistic approach including Computational Genomics, In silico Modeling and Functional Genomics in order to test whether treatment-resistant subclones emerge in recurrent tumors, and characterize them in clinically relevant ways in multiple patients. And this is just a glimpse of what is discussed in this Episode.
References
- Lucy F. Stead, Helene Thygesen, … Pamela Rabbitts (2015) Using common variants to indicate cancer genes (International Journal of Cancer) DOI: 10.1002/ijc.28951
- Caroline Conway, Jennifer L. Graham, … Lucy F. Stead (2015) Elucidating drivers of oral epithelial dysplasia formation and malignant transformation to cancer using RNAseq (Oncotarget) DOI: 10.18632/oncotarget.5529
- Alastair Droop, Alexander Bruns, … Lucy F. Stead (2018) How to analyse the spatiotemporal tumour samples needed to investigate cancer evolution: A case study using paired primary and recurrent glioblastoma (International Journal of Cancer) DOI: 10.1002/ijc.31184
- Georgette Tanner, David R. Westhead, … Lucy F. Stead (2019) Simulation of heterogeneous tumour genomes with HeteroGenesis and in silico whole exome sequencing (Bioinformatics (Oxford, England)) DOI: 10.1093/bioinformatics/bty1063
- Nora Rippaus, Alexander F-Bruns, … Lucy F. Stead (2019) JARID2 facilitates transcriptional reprogramming in glioblastoma in response to standard treatment (bioRxiv) DOI: 10.1101/649400
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Joe Fernandez, the founder of Active Motif, has played a significant role in the evolution of the biotechnology industry. He’s seen where the industry has been, and he has a good idea where it’s going.
Prior to founding Active Motif in 1999, Joe was a co-founder of Invitrogen where he helped revolutionize molecular cloning with the TOPO TA kit. Joe’s passion for disrupting established workflows by making them easier and more efficient didn’t stop there. With Active Motif, he launched the first ever ChIP kit in 2003, and the company now offers the most complete portfolio of ChIP kits for different workflows and sample types, the highest quality ChIP-validated antibodies, and the most comprehensive and most cited end-to-end Epigenetic Services.
In this interview, we sat down with Joe to learn how he got started in science, what he’s currently excited about, and what he thinks will be the next big thing in epigenetics research.
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In this Episode of the Epigenetics Podcast our guest Ana Pombo from the Max-Delbrück-Center in Berlin provides insight in her work on the interplay between gene regulation and genome architecture. To do so she and her team use different state of the art methods, including cryo-sectioning to unravel this regulatory network. In 2006, they proposed the Interchromatin Network Model of chromosome organization which postulates that chromosome folding is driven by contacts between different genomic regions and between chromatin and nuclear landmarks, such as the nuclear lamina. And later on they used polymer physics modeling to study those mechanisms, which lead to the development of the Strings & Binders Switch (SBS) model. And this is just a glimpse of the topics that are discussed in this Episode.
References * Miguel R. Branco, Ana Pombo (2006) Intermingling of Chromosome Territories in Interphase Suggests Role in Translocations and Transcription-Dependent Associations (PLOS Biology) DOI: 10.1371/journal.pbio.0040138 * Robert A. Beagrie, Ana Pombo (2016) Gene activation by metazoan enhancers: Diverse mechanisms stimulate distinct steps of transcription (BioEssays: News and Reviews in Molecular, Cellular and Developmental Biology) DOI: 10.1002/bies.201600032 * Emily Brookes, Inês de Santiago, … Ana Pombo (2012) Polycomb Associates Genome-wide with a Specific RNA Polymerase II Variant, and Regulates Metabolic Genes in ESCs (Cell Stem Cell) DOI: 10.1016/j.stem.2011.12.017 * Mario Nicodemi, Ana Pombo (2014) Models of chromosome structure (Current Opinion in Cell Biology) DOI: 10.1016/j.ceb.2014.04.004 - Robert A. Beagrie, Antonio Scialdone, … Ana Pombo (2017) Complex multi-enhancer contacts captured by genome architecture mapping (Nature) DOI: 10.1038/nature21411
Contact * https://twitter.com/activemotif * https://twitter.com/epigenetics_pod * https://www.linkedin.com/company-beta/35651/ * https://www.facebook.com/ActiveMotifInc/ * eurotech@activemotif.com
Dosage compensation is an essential process to regulate the gene expression of the X-chromosome in female and male flies. Thereby the mechanism of regulation in humans and in drosophila is different. In humans one X-chromosome is randomly shut down in females compared to men, whereas in drosophila equilibrium is achieved by overexpression of the single X-chromosome in males. In this Episode our guest Dr. Asifa Akhtar provides information on her work on dosage compensation in drosophila melanogaster and how the MSL-complex, the Histone-acetyltransferase MOF work together in this process. Furthermore, she also talks about potential functions of those Proteins in the human system.
References
- Jan Kadlec, Erinc Hallacli, … Asifa Akhtar (2011) Structural basis for MOF and MSL3 recruitment into the dosage compensation complex by MSL1 (Nature Structural & Molecular Biology) DOI: 10.1038/nsmb.1960
- Thomas Conrad, Florence M.G. Cavalli, … Asifa Akhtar (2012) The MOF Chromobarrel Domain Controls Genome-wide H4K16 Acetylation and Spreading of the MSL Complex (Developmental Cell) DOI: 10.1016/j.devcel.2011.12.016
- Maria Samata, Asifa Akhtar (2018) Dosage Compensation of the X Chromosome: A Complex Epigenetic Assignment Involving Chromatin Regulators and Long Noncoding RNAs (Annual Review of Biochemistry) DOI: 10.1146/annurev-biochem-062917-011816
- Bilal N. Sheikh, Sukanya Guhathakurta, Asifa Akhtar (2019) The non-specific lethal (NSL) complex at the crossroads of transcriptional control and cellular homeostasis (EMBO reports) DOI: 10.15252/embr.201847630
- Kin Chung Lam, Ho-Ryun Chung, … Asifa Akhtar (2019) The NSL complex-mediated nucleosome landscape is required to maintain transcription fidelity and suppression of transcription noise (Genes & Development) DOI: 10.1101/gad.321489.118
- Claudia Isabelle Keller Valsecchi, M. Felicia Basilicata, … Asifa Akhtar (2018) Facultative dosage compensation of developmental genes on autosomes in Drosophila and mouse embryonic stem cells (Nature Communications) DOI: 10.1038/s41467-018-05642-2
Contact
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In recent years it has become more and more evident, that genome folding and chromatin packaging into the nucleus plays a pivotal role in the regulation of gene expression. In this Episode of our Podcast our host Dr. Stefan Dillinger spoke with Professor Wendy Bickmore about her work on the spatial organization of the human genome. Prof. Bickmore and her team mainly use visual methods like fluorescence in situ hybridisation (FISH) to study the organization of chromosomes in human and murine cells and how they contribute to transcriptional regulation and how this organization changes during ageing, development or disease.
References
- Charlene Boumendil, Priya Hari, … Wendy A. Bickmore (2019) Nuclear pore density controls heterochromatin reorganization during senescence (Genes & Development) DOI: 10.1101/gad.321117.118
- Charlene Lemaître, Wendy A. Bickmore (2015) Chromatin at the nuclear periphery and the regulation of genome functions (Histochemistry and Cell Biology) DOI: 10.1007/s00418-015-1346-y
- James Fraser, Iain Williamson, … Josée Dostie (2015) An Overview of Genome Organization and How We Got There: from FISH to Hi-C (Microbiology and Molecular Biology Reviews) DOI: 10.1128/MMBR.00006-15
- Emmanuelle Deniaud, Wendy A Bickmore (2009) Transcription and the nuclear periphery: edge of darkness? (Current Opinion in Genetics & Development) DOI: 10.1016/j.gde.2009.01.005
- Nicola L. Mahy, Paul E. Perry, … Wendy A. Bickmore (2002) Spatial organization of active and inactive genes and noncoding DNA within chromosome territories (The Journal of Cell Biology) DOI: 10.1083/jcb.200111071
Contact
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Heterochromatin plays a pivotal role in organizing our genome in the nucleus and separating active from inactive genomic regions. In this Podcast Episode our Guest Gary Karpen from UC Berkeley sits down with our Host Stefan Dillinger to talk about the regulation of this chromatin structure and how DNA repair mechanisms function in this densely packed nuclear compartment. Furthermore, they also discuss how phase separation might be an important part in how heterochromatin domains are formed.
References
- Jamy C. Peng, Gary H. Karpen (2009) Heterochromatic Genome Stability Requires Regulators of Histone H3 K9 Methylation (PLoS Genetics) DOI: 10.1371/journal.pgen.1000435
- Peter V. Kharchenko, Artyom A. Alekseyenko, … Peter J. Park (2011) Comprehensive analysis of the chromatin landscape in Drosophila melanogaster (Nature) DOI: 10.1038/nature09725
- Aniek Janssen, Serafin U. Colmenares, … Gary H. Karpen (2019) Timely double-strand break repair and pathway choice in pericentromeric heterochromatin depend on the histone demethylase dKDM4A (Genes & Development) DOI: 10.1101/gad.317537.118
- Amy R. Strom, Alexander V. Emelyanov, … Gary H. Karpen (2017) Phase separation drives heterochromatin domain formation (Nature) DOI: 10.1038/nature22989
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Type 2 Diabetes (T2D) is a chronic metabolic disease, which is caused by the failure of beta-cells in the pancreas and insulin resistance in peripheral tissue and characterized by high glucose levels in the blood. World-wide 382 Million people suffer from Diabetes which makes up 8,3% of the population. Due to this high proportion it is of high interest to find a cure for this disease.
The restoration of β-cell mass and function has therefore become a field of intensive research seeking for the next generation of anti-diabetic drugs. Tremendous efforts have been made on deciphering epigenetic regulations that control metabolic tissue function. For several years, the team led by Dr. Jean-Sebastien Annicotte has dissected the molecular links between insulin producing cells, insulin target tissues and T2D/obesity development. Especially, the team research has been focused on the role of cell cycle regulators and their transcriptional co-regulators in the control of metabolic homeostasis, T2D and obesity.
References
- Jean-Sébastien Annicotte, Elisabeth Fayard, … Johan Auwerx (2003) Pancreatic-Duodenal Homeobox 1 Regulates Expression of Liver Receptor Homolog 1 during Pancreas Development (Molecular and Cellular Biology) DOI: 10.1128/MCB.23.19.6713-6724.2003
- Jean-Sébastien Annicotte, Emilie Blanchet, … Lluis Fajas (2009) The CDK4-pRB-E2F1 pathway controls insulin secretion (Nature Cell Biology) DOI: 10.1038/ncb1915
- Emilie Blanchet, Jean-Sébastien Annicotte, … Lluis Fajas (2011) E2F transcription factor-1 regulates oxidative metabolism (Nature Cell Biology) DOI: 10.1038/ncb2309
- Nabil Rabhi, Pierre-Damien Denechaud, … Jean-Sébastien Annicotte (2016) KAT2B Is Required for Pancreatic Beta Cell Adaptation to Metabolic Stress by Controlling the Unfolded Protein Response (Cell Reports) DOI: 10.1016/j.celrep.2016.03.079
- Albert Giralt, Pierre-Damien Denechaud, … Lluis Fajas (2018) E2F1 promotes hepatic gluconeogenesis and contributes to hyperglycemia during diabetes (Molecular Metabolism) DOI: 10.1016/j.molmet.2018.02.011
Contact
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In the seventh Episode of Active Motif's Epigenetics Podcast our host Dr. Stefan Dillinger sat down with Prof. Edith Heard, designated Director General of the European Molecular Biology Laboratory (EMBL), to talk about the challenges and goals of her new position as Director General of the EMBL. Furthermore, they also talk about her research on X-inactivation and dosage compensation.
References
- Heard Lab - https://science.institut-curie.org/research/biology-cancer-genetics-and-epigenetics/developmental-biology-and-genetics/team-heard/
- Elphège P. Nora, Bryan R. Lajoie, … Edith Heard (2012) Spatial partitioning of the regulatory landscape of the X-inactivation centre (Nature) DOI: 10.1038/nature11049
- Luca Giorgetti, Bryan R. Lajoie, … Job Dekker (2016) Structural organization of the inactive X chromosome in the mouse (Nature) DOI: 10.1038/nature18589
- Luca Giorgetti, Rafael Galupa, … Edith Heard (2014) Predictive Polymer Modeling Reveals Coupled Fluctuations in Chromosome Conformation and Transcription (Cell) DOI: 10.1016/j.cell.2014.03.025
- Maud Borensztein, Laurène Syx, … Edith Heard (2017) Xist-dependent imprinted X inactivation and the early developmental consequences of its failure (Nature Structural & Molecular Biology) DOI: 10.1038/nsmb.3365
Contact
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In the sixth Episode of Active Motif's Epigenetics Podcast our host Dr. Stefan Dillinger sits down with Prof. Susan Gasser, director of the Friedrich Miescher Institute in Basel, to talk about her research on heterochromatin, its localization in the nucleus and factors that are involved in the anchoring genomic regions at the nuclear periphery.
References
- Gasser Lab - https://www.fmi.ch/research/groupleader/website/gasserlab/researchtopics.php
- Peter Zeller, Jan Padeken, … Susan M. Gasser (2016) Histone H3K9 methylation is dispensable for Caenorhabditis elegans development but suppresses RNA:DNA hybrid-associated repeat instability (Nature Genetics) DOI: 10.1038/ng.3672
- Adriana Gonzalez-Sandoval, Benjamin D. Towbin, … Susan M. Gasser (2015) Perinuclear Anchoring of H3K9-Methylated Chromatin Stabilizes Induced Cell Fate in C. elegans Embryos (Cell) DOI: 10.1016/j.cell.2015.10.066
- Benjamin D. Towbin, Cristina González-Aguilera, … Susan M. Gasser (2012) Step-Wise Methylation of Histone H3K9 Positions Heterochromatin at the Nuclear Periphery (Cell) DOI: 10.1016/j.cell.2012.06.051
Contact
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In the fifth Episode of the Epigenetics Podcast of Active Motif our host Dr. Stefan Dillinger sits down with Prof. Henk Stunnenberg, full professor and head of the Department of Molecular Biology at the Radboud University in Nijmegen, to talk about his research in Epigenetics and his contributions to the BLUEPRINT and Human Cell Atlas consortia.
References
- Stunnenberg Lab - http://molbio.science.ru.nl/about/molecular-biology/henk-stunnenberg/
- The Blueprint Consortium - http://www.blueprint-epigenome.eu
- Human Cell Atlas - https://www.humancellatlas.org/
- Hendrik G. Stunnenberg, Sergio Abrignani, … Martin Hirst (2016) The International Human Epigenome Consortium: A Blueprint for Scientific Collaboration and Discovery (Cell) DOI: 10.1016/j.cell.2016.11.007
Contact
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The aging population and challenges that arise from aging are one of the great scientific challenges of this time. In the fourth episode of the Epigenetics Podcast from Active Motif, our host Dr. Stefan Dillinger talks with Dr. Peter Tessarz from the Max Planck Institute for Biology of Ageing about his contributions to the field of aging and also, which epigenetic factors play a role in this process.
References for this episode: * Tessarz Lab: https://www.age.mpg.de/science/research-labs/tessarz/ * Hayflick, Moorhead. 1961. The serial cultivation of human diploid cell strains. Exp Cell Res. Dec;25:585-621. * Donna Lowe, Steve Horvath and Kenneth Raj. 2016. Epigenetic clock analyses of cellular senescence and ageing. Oncotarget. 2016; 7:8524-8531. https://doi.org/10.18632/oncotarget.7383 * Peter Tessarz, Helena Santos-Rosa, … Tony Kouzarides. 2014. Glutamine methylation in histone H2A is an RNA-polymerase-I-dedicated modification. Nature. 2014 Jan 23; 505, 564–568. doi:10.1038/nature12819 * Peter Tessarz, Tony Kouzarides. 2014. Histone core modifications regulating nucleosome structure and dynamics. Nature Reviews Molecular Cell Biology. 2014 Oct 15: 15, 703–708. doi:10.1038/nrm3890 * Payel Sen, Parisha P. Shah, Rafaella Nativio, & Shelley L. Berger. 2016. Epigenetic Mechanisms of Longevity and Aging. Cell. 2016 Aug 11: 166,4,822-839. DOI: http://dx.doi.org/10.1016/j.cell.2016.07.050
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Cancer has become one of the most dangerous diseases of the aging population of industrialized countries. Finding tools to fight cancer is hard, because Cancer presents itself as highly heterogeneous, with over 100 types of cancers described. Not only does Cancer affect aged humans, it has been observed in children in the form of e.g. Medulloblastoma. In the third episode of Active Motif's Epigenetics Podcast, our host Dr. Stefan Dillinger sits down with Dr. David Jones, group leader at the German Cancer Research Center in Heidelberg, to talk about his research on Medulloblastoma and also the emerging role of epigenetic factors in Cancer.
References for this episode * Alioto, Ivo Buchhalter, … Ivo G. Gut. A comprehensive assessment of somatic mutation detection in cancer using whole-genome sequencing. Nature Communications. 2015 Dec 9; 6, Article number: 10001 doi:10.1038/ncomms10001 * David TW Jones, Natalie Jäger, … Peter Lichter. ICGC PedBrain: Dissecting the genomic complexity underlying medulloblastoma. Nature. 2012 Aug 2; 488(7409): 100–105. doi:10.1038/nature11284 * Jeremy Schwartzentruber, Andrey Korshunov, … Nada Jabado. Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma. Nature. 2012 Feb 9; 482, 226–231 doi:10.1038/nature10833
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The Nucleosome is the basic building unit of chromatin. It consists out of 147 base pairs of double stranded DNA wrapped around the Histone core octamer that consists out of 2 copies of each dimer of H2A/H2B, and H3/H4. Nucleosomes are organized like "beads on a string" to form a modifiable regulatory basis for higher order structures of chromatin. The first images of the nucleosome as a particle was published by our guests Ada and Don Olins from the University of New England in 1974 (Olins, A. L. & Olins, D. E. Spheroid Chromatin Units (ν Bodies). Science 183, 330–332 (1974).). This observation lead the way to numerous discoveries around chromatin which ultimately culminated in the discovery of the 2.8 Angstrom high-resolution crystal structure 20 years ago in the year 1997 (Luger, K., Mäder, A. W., Richmond, R. K., Sargent, D. F. & Richmond, T. J. Crystal structure of the nucleosome core particle at 2.8 Å resolution. Nature 389, 251–260 (1997).)
References for this episode * Ada L. Olins, Donald E. Olins. Spheroid Chromatin Units (ν Bodies). Science. 25 Jan 1974: Vol. 183, Issue 4122, pp. 330-332. DOI: 10.1126/science.183.4122.330 * Ada L. Olins, Donald E. Olins, et al. An epichromatin epitope. Nucleus. 2011 Jan-Feb; 2(1): 47–60. DOI: 10.4161/nucl.2.1.13271
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Chromatin Immunoprecipitation (ChIP) was first developed in Drosophila, where interactions of RNA Pol II with genes were investigated (Mol. Cell. Biol. August 1985 vol. 5 no. 8 2009-2018). Then, in a 1993 publication, (Genes & Dev. 1993 7:592-604), the group of James Broach described the association of histone acetylation state with transcriptional gene silencing in yeast. The technique was first used successfully in mammalian cells by Richard Treisman's group, published in 1998 (Cell (1998) 92:475-87).
Chromatin Immunoprecipitation is used to link specific states of chromatin to individual loci in a cell, to understand how genes are regulated, and to decipher the Histone Code. In this Episode, we discuss the multiple challenges of ChIP experiments and the difficulties that can arise during different steps of the process.
References for this episode Epigenetics News:
- Chung-Chau Hon, Jordan A. Ramilowski, … Alistair R. R. Forrest. An atlas of human long non-coding RNAs with accurate 5′ ends. Nature. March 2017. doi:10.1038/nature21374
- Jennifer L. Guerriero, Alaba Sotayo, … Anthony Letai. Class IIa HDAC inhibition reduces breast tumours and metastases through anti-tumour macrophages. Nature. March 2017. doi:10.1038/nature21409
- Nitika Taneja, Martin Zofall, … Shiv I. S. Grewal. SNF2 Family Protein Fft3 Suppresses Nucleosome Turnover to Promote Epigenetic Inheritance and Proper Replication. Molecular Cell. April 2017. DOI:10.1016/j.molcel.2017.02.006
Multiple Challenges in ChIP
- D. S. Gilmour, J. T. Lis. In vivo interactions of RNA polymerase II with genes of Drosophila melanogaster. Molecular and Cellular Biology. August 1985. doi:10.1128/MCB.5.8.2009
- M. Braunstein, A. B. Rose, … J. R. Broach. Transcriptional silencing in yeast is associated with reduced nucleosome acetylation. Genes & Development. 1993. doi:10.1101/gad.7.4.592
- Arthur S. Alberts, Olivier Geneste, Richard Treisman. Activation of SRF-Regulated Chromosomal Templates by Rho-Family GTPases Requires a Signal that Also Induces H4 Hyperacetylation. Cell. February 1986. doi:10.1016/S0092-8674(00)80941-1
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