R-Loop Biology in Health and Disease (Natalia Gromak)

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: [email protected]

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)   Contact Epigenetics Podcast on Mastodon Epigenetics Podcast on Bluesky Dr. Stefan Dillinger on LinkedIn Active Motif on LinkedIn Active Motif on Bluesky Email: [email protected]

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)   Contact Epigenetics Podcast on Instagram Epigenetics Podcast on Mastodon Epigenetics Podcast on Bluesky Dr. Stefan Dillinger on LinkedIn Active Motif on LinkedIn Active Motif on Bluesky Email: [email protected]

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!   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: [email protected]

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: [email protected]

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   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: [email protected]

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)   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: [email protected]

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)   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: [email protected]

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)   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: [email protected]

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)   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: [email protected]