Epigenetics Podcast

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]