Epigenetics Podcast

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 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

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 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 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 Downstr

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. 20

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