The Effect of Vitamin D on the Epigenome (Folami Ideraabdullah)

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: [email protected]

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)   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 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: [email protected]

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)   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 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)   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 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: [email protected]

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)   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 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)   Contact Epigenetics Podcast on X Epigenetics Podcast on Instagram Epigenetics Podcast on Mastodon Epigenetics Podcast on Bluesky Epigenetics Podcast on Threads Active Motif on Twitter Active Motif on LinkedIn Email: [email protected]

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)   Contact Epigenetics Podcast on Twitter Epigenetics Podcast on Instagram Epigenetics Podcast on Mastodon Epigenetics Podcast on Bluesky Active Motif on Twitter Active Motif on LinkedIn Email: [email protected]

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)   Contact Epigenetics Podcast on Twitter/X Epigenetics Podcast on Instagram Epigenetics Podcast on Mastodon Epigenetics Podcast on Bluesky Active Motif on Twitter Active Motif on LinkedIn Email: [email protected]