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.

Magnani, L., Stoeck, A., Zhang, X., Lánczky, A., Mirabella, A. C., Wang, T. L., Gyorffy, B., & Lupien, M. (2013). Genome-wide reprogramming of the chromatin landscape underlies endocrine therapy resistance in breast cancer. Proceedings of the National Academy of Sciences of the United States of America, 110(16), E1490–E1499. https://doi.org/10.1073/pnas.1219992110

Nguyen, V. T., Barozzi, I., Faronato, M., Lombardo, Y., Steel, J. H., Patel, N., Darbre, P., Castellano, L., Győrffy, B., Woodley, L., Meira, A., Patten, D. K., Vircillo, V., Periyasamy, M., Ali, S., Frige, G., Minucci, S., Coombes, R. C., & Magnani, L. (2015). Differential epigenetic reprogramming in response to specific endocrine therapies promotes cholesterol biosynthesis and cellular invasion. Nature communications, 6, 10044. https://doi.org/10.1038/ncomms10044

Patten, D. K., Corleone, G., & Magnani, L. (2018). Chromatin Immunoprecipitation and High-Throughput Sequencing (ChIP-Seq): Tips and Tricks Regarding the Laboratory Protocol and Initial Downstream Data Analysis. Methods in molecular biology (Clifton, N.J.), 1767, 271–288. https://doi.org/10.1007/978-1-4939-7774-1_15

Enhancers and Chromatin Remodeling in Mammary Gland Development (Camila dos Santos)

Contribution of Estrogen Receptor to Breast Cancer Progression (Jason Carroll)

Circulating Epigenetic Biomarkers in Cancer (Charlotte Proudhon)

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In this episode of the Epigenetics Podcast, we talked with Erica Korb from the University of Pennsylvania about her work on BRD4 and the histone variant H2BE, which influences synaptic genes and neuronal activity.

Dr. Korb discusses the focus of her lab, which centers on epigenetic mechanisms impacting gene regulation in neurons. Her research primarily examines histone biology and its connection to neurodevelopmental disorders, including autism spectrum disorder and intellectual disabilities. Dr. Korb expounds on the collaborative environment at UPenn’s Epigenetics Institute, emphasizing how the rich diversity of research topics fosters innovative ideas and projects within the community.

Reflecting on her earlier work from her postdoctoral studies, Dr. Korb discusses her first significant findings regarding the protein BRD4. This work demonstrated BRD4's role in mediating transcriptional regulation crucial for learning and memory processes. She explains how disrupting this protein's function in neurons hindered critical gene activations required for memory formation in mice. This foundational understanding opened avenues for exploring the broader implications of chromatin regulation in various neurodevelopmental conditions.

Transitioning into her current research endeavors, Dr. Korb reveals how she aims to expand her focus beyond Fragile X syndrome. With her lab now investigating multiple chromatin regulators implicated in various forms of autism spectrum disorders, she describes a recent project where RNA sequencing exposed substantial overlaps in gene expression changes associated with five distinct chromatin modifiers, each contributing uniquely to neuronal function while collectively demonstrating sensitivity to chromatin disruptions.

A significant portion of the discussion centers around Dr. Korb’s unexpected exploration into how COVID-19 intersects with chromatin biology through a phenomenon known as histone mimicry. Leveraging bioinformatic tools during the pandemic, her lab discovered that certain viral proteins mimic histone sequences, which may lead to altered transcriptional outputs in host cells. This coincidental finding illustrates both the creative adaptability needed in scientific research and the importance of collaborative efforts across disciplines to uncover new insights.

The conversation also delves into Dr. Korb’s recent work regarding the histone variant H2BE, initiated by one of her graduate students. She explains how prior research only recognized H2BE's expression in the olfactory system, yet her lab has demonstrated its significant role in regulating synaptic genes and memory formation throughout broader neuronal contexts. Notably, they identified a single amino acid change that influences H2BE's function in chromatin accessibility and gene transcription, emphasizing its potential evolutionary conservation across species.

In terms of H2BE's role, Dr. Korb elucidates that its activity is integral in response to extracellular stimuli, particularly within the context of neuronal activation. Intriguingly, they found that H2BE expression decreases in reaction to long-term neuronal stimulation, suggesting a complex mechanism of homeostatic plasticity crucial for regulating neuronal activity levels. This research not only advances understanding of chromatin dynamics but also holds implications for neuronal health and disease mechanisms.

Feierman, E. R., Louzon, S., Prescott, N. A., Biaco, T., Gao, Q., Qiu, Q., Choi, K., Palozola, K. C., Voss, A. J., Mehta, S. D., Quaye, C. N., Lynch, K. T., Fuccillo, M. V., Wu, H., David, Y., & Korb, E. (2024). Histone variant H2BE enhances chromatin accessibility in neurons to promote synaptic gene expression and long-term memory. Molecular cell, 84(15), 2822–2837.e11. https://doi.org/10.1016/j.molcel.2024.06.025

Korb, E., Herre, M., Zucker-Scharff, I., Gresack, J., Allis, C. D., & Darnell, R. B. (2017). Excess Translation of Epigenetic Regulators Contributes to Fragile X Syndrome and Is Alleviated by Brd4 Inhibition. Cell, 170(6), 1209–1223.e20. https://doi.org/10.1016/j.cell.2017.07.033

Kee, J., Thudium, S., Renner, D. M., Glastad, K., Palozola, K., Zhang, Z., Li, Y., Lan, Y., Cesare, J., Poleshko, A., Kiseleva, A. A., Truitt, R., Cardenas-Diaz, F. L., Zhang, X., Xie, X., Kotton, D. N., Alysandratos, K. D., Epstein, J. A., Shi, P. Y., Yang, W., … Korb, E. (2022). SARS-CoV-2 disrupts host epigenetic regulation via histone mimicry. Nature, 610(7931), 381–388. https://doi.org/10.1038/s41586-022-05282-z

Feierman, E. R., Paranjapye, A., Su, S., Qiu, Q., Wu, H., & Korb, E. (2024). Histone variant H2BE controls activity-dependent gene expression and homeostatic scaling. bioRxiv : the preprint server for biology, 2024.11.01.620920. https://doi.org/10.1101/2024.11.01.620920

Neuroepigenetic Mechanisms and Primate Epigenome Evolution (Boyan Bonev)

DNA Methylation Alterations in Neurodegenerative Diseases (Paula Desplats)

The Role of Histone Dopaminylation and Serotinylation in Neuronal Plasticity (Ian Maze)

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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.

Mozo T, Dewar K, Dunn P, Ecker JR, Fischer S, Kloska S, Lehrach H, Marra M, Martienssen R, Meier-Ewert S, Altmann T. A complete BAC-based physical map of the Arabidopsis thaliana genome. Nat Genet. 1999 Jul;22(3):271-5. doi: 10.1038/10334. PMID: 10391215.

Zhang X, Yazaki J, Sundaresan A, Cokus S, Chan SW, Chen H, Henderson IR, Shinn P, Pellegrini M, Jacobsen SE, Ecker JR. Genome-wide high-resolution mapping and functional analysis of DNA methylation in arabidopsis. Cell. 2006 Sep 22;126(6):1189-201. doi: 10.1016/j.cell.2006.08.003. Epub 2006 Aug 31. PMID: 16949657.

Lister R, O'Malley RC, Tonti-Filippini J, Gregory BD, Berry CC, Millar AH, Ecker JR. Highly integrated single-base resolution maps of the epigenome in Arabidopsis. Cell. 2008 May 2;133(3):523-36. doi: 10.1016/j.cell.2008.03.029. PMID: 18423832; PMCID: PMC2723732.

Lister R, Pelizzola M, Dowen RH, Hawkins RD, Hon G, Tonti-Filippini J, Nery JR, Lee L, Ye Z, Ngo QM, Edsall L, Antosiewicz-Bourget J, Stewart R, Ruotti V, Millar AH, Thomson JA, Ren B, Ecker JR. Human DNA methylomes at base resolution show widespread epigenomic differences. Nature. 2009 Nov 19;462(7271):315-22. doi: 10.1038/nature08514. Epub 2009 Oct 14. PMID: 19829295; PMCID: PMC2857523.

Lister R, Pelizzola M, Kida YS, Hawkins RD, Nery JR, Hon G, Antosiewicz-Bourget J, O'Malley R, Castanon R, Klugman S, Downes M, Yu R, Stewart R, Ren B, Thomson JA, Evans RM, Ecker JR. Hotspots of aberrant epigenomic reprogramming in human induced pluripotent stem cells. Nature. 2011 Mar 3;471(7336):68-73. doi: 10.1038/nature09798. Epub 2011 Feb 2. Erratum in: Nature. 2014 Oct 2;514(7520):126. PMID: 21289626; PMCID: PMC3100360.

Epigenetic Reprogramming During Mammalian Development (Wolf Reik)

Single Cell Epigenomics in Neuronal Development (Tim Petros)

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In this episode of the Epigenetics Podcast, we talked with Sarah Teichmann from the University of Cambridge about the Human Cell Atlas.

In the Interview we explore Sarah Teichmann's impressive career trajectory, covering her current role as Chair of Stem Cell Medicine at the Cambridge Stem Cell Institute and Vice President of Translational Research at GlaxoSmithKline. Professor Teichmann explains her unique dual appointments, a rare arrangement that allows her to bridge academia and industry effectively.

As the conversation shifts focus to computational biology, she takes us on a historical journey from her PhD work at the MRC Laboratory of Molecular Biology to the present advancements driven by next-generation sequencing and artificial intelligence methods. Professor Teichmann emphasizes that the landscape of biological research has evolved significantly, particularly in the realm of data-driven methodologies.

The conversation then transitions seamlessly into her pivotal role in advancing single-cell genomics, where she discusses the motivation behind using single-cell RNA sequencing methods in her research on T cells. This technique offered unmatched insights compared to bulk sequencing techniques, allowing for a more detailed understanding of cell states and their complex interactions within tissues.

A highlight of the episode is Professor Teichmann's insights on the Human Cell Atlas project, which she co-founded in 2017. She elaborates on the ambitious vision to map all human cells, likening the endeavor to the Human Genome Project. Through the atlas, researchers aim to create a detailed reference map that facilitates a deeper understanding of human health and disease. Professor Teichmann shares the collaborative efforts that led to its inception and the importance of international cooperation in scientific research.

The discussion culminates with an exploration of the biggest scientific findings thus far from the Human Cell Atlas. Among the revelations, she notes the astounding complexity and diversity of cell types identified, particularly within the immune system, and the unexpected locations of certain cell types during human development. She also highlights significant discoveries related to COVID-19, demonstrating the immediate real-world impact of their work.

https://www.humancellatlas.org

The Human Cell Atlas: towards a first draft atlas

Kock, K. H., Tan, L. M., Han, K. Y., Ando, Y., Jevapatarakul, D., Chatterjee, A., Lin, Q. X. X., Buyamin, E. V., Sonthalia, R., Rajagopalan, D., Tomofuji, Y., Sankaran, S., Park, M. S., Abe, M., Chantaraamporn, J., Furukawa, S., Ghosh, S., Inoue, G., Kojima, M., Kouno, T., … Prabhakar, S. (2025). Asian diversity in human immune cells. Cell, 188(8), 2288–2306.e24. https://doi.org/10.1016/j.cell.2025.02.017

The Discovery of Genomic Imprinting (Azim Surani)

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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.

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.

Epigenetic Reprogramming During Mammalian Development (Wolf Reik)

Epigenetic and Metabolic Regulation of Early Development (Jan Żylicz)

Epigenetic Mechanisms in Genome Regulation and Developmental Programming (James Hackett)

Epigenetic Mechanisms of Mammalian Germ Cell Development (Mitinori Saitou)

Exploring DNA Methylation and TET Enzymes in Early Development (Petra Hajkova)

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In this episode of the Epigenetics Podcast, we talked with Petra Hajkova from the MRC Laboratory of Medical Sciences about her work on epigenetics research on mammalian development, highlighting DNA methylation, histone modifications, and TET enzymes, along with her journey in molecular genetics and future research on epigenetic maintenance.

Dr. Hajkova's early work focused on DNA methylation and resulted in innovative collaboration that allowed her to develop bisulfide sequencing techniques. We discuss her transition to the UK, where she began working in Azim Surani's lab at the University of Cambridge. Dr. Hajkova describes the excitement of researching chromatin dynamics in the mouse germline, leading to significant findings published in Nature. Her story highlights the intense yet rewarding nature of postdoctoral research as she navigated the complexities of working with embryos for the first time.

As her research progressed, Dr. Hajkova established her own lab at the MRC London Institute of Medical Sciences, where she became a professor in 2017. We delve into her investigations on the differences between embryonic stem cells and embryonic germ cells regarding their distinct developmental origins. Dr. Hajkova outlines the challenges she faced in understanding the mechanisms behind global DNA demethylation in germline cells and the role of hydroxymethylation during early development.

The discussion further covers her exciting findings regarding the specific functions of TET enzymes and their regulatory roles in maintaining epigenetic states. We explore her recent research published in Nature, which provides insights into the transition from primordial germ cells to gonocytes, emphasizing the significance of various epigenetic mechanisms in germline development.

Hajkova P, Ancelin K, Waldmann T, Lacoste N, Lange UC, Cesari F, Lee C, Almouzni G, Schneider R, Surani MA. Chromatin dynamics during epigenetic reprogramming in the mouse germ line. Nature. 2008 Apr 17;452(7189):877-81. doi: 10.1038/nature06714. Epub 2008 Mar 19. PMID: 18354397; PMCID: PMC3847605.

Hajkova P, Jeffries SJ, Lee C, Miller N, Jackson SP, Surani MA. Genome-wide reprogramming in the mouse germ line entails the base excision repair pathway. Science. 2010 Jul 2;329(5987):78-82. doi: 10.1126/science.1187945. PMID: 20595612; PMCID: PMC3863715.

Hill PWS, Leitch HG, Requena CE, Sun Z, Amouroux R, Roman-Trufero M, Borkowska M, Terragni J, Vaisvila R, Linnett S, Bagci H, Dharmalingham G, Haberle V, Lenhard B, Zheng Y, Pradhan S, Hajkova P. Epigenetic reprogramming enables the transition from primordial germ cell to gonocyte. Nature. 2018 Mar 15;555(7696):392-396. doi: 10.1038/nature25964. Epub 2018 Mar 7. PMID: 29513657; PMCID: PMC5856367.

Huang TC, Wang YF, Vazquez-Ferrer E, Theofel I, Requena CE, Hanna CW, Kelsey G, Hajkova P. Sex-specific chromatin remodelling safeguards transcription in germ cells. Nature. 2021 Dec;600(7890):737-742. doi: 10.1038/s41586-021-04208-5. Epub 2021 Dec 8. PMID: 34880491.

Epigenetic Mechanisms of Mammalian Germ Cell Development (Mitinori Saitou)

Epigenetic Reprogramming During Mammalian Development (Wolf Reik)

DNA Methylation and Mammalian Development (Déborah Bourc'his)

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In this episode of the Epigenetics Podcast, we talked with Ani Deshpande from Sanford Burnham Prebys about his work on epigenetic regulation and developing small molecules through high throughput screens for AML.

Throughout our discussion, we delve into Dr. Despande's journey into the field of biology and science, tracing his evolution from a literature enthusiast in Mumbai to a dedicated cancer researcher. He reflects on his formative experiences during his PhD at Ludwig Maximilian University in Munich, where she developed murine models for refractory acute myeloid leukemia (AML). We examine these models' contributions to therapeutic discovery and understanding the intricate mechanisms underscoring AML's complexities.

Transitioning to his postdoctoral work at Scott Armstrong's lab in Boston, Dr. Despande shares his insights on the importance of epigenetic regulators, such as DOT1L, in leukemias, and how they can serve as strategic therapeutic targets. His ambitious pursuit of translational research is further highlighted through his efforts in developing a conditional knockout mouse model and his collaborative work utilizing CRISPR technology to refine our understanding of epigenetic regulation in cancer pathogenesis.

Moreover, we engage in a conversation about the challenges and opportunities that arise when establishing his lab at Sanford Burnham Prebys. Dr. Despande candidly discusses the delicate balance between pursuing topics of genuine interest versus adhering to grant fundability, underlining the tension researchers face in the current scientific landscape. His emphasis on the critical need for innovation within lab settings serves as a motivational call for emerging scientists to venture beyond the established templates that often inhibit groundbreaking discoveries.

We conclude our dialogue with an exploration of his recent projects, which involve targeting specific epigenetic modifiers and how his lab’s findings can contribute to greater understanding and potential treatments for not only AML but also other pediatric cancers driven by gene fusions. Dr. Despande's insights into the integration of modern technologies, such as CRISPR libraries, exemplify his commitment to pushing the boundaries of cancer research.

In addition to discussing his scientific contributions, we touch upon Dr. Despande's foray into podcasting (The Discovery Dialogues), shedding light on his motivation to bridge the communication gap between scientists and the broader public. He articulates his desire to demystify scientific discoveries and promote awareness about the intricate journey of research that lays the groundwork for medical advancements. This multidimensional discussion not only highlights his scientific achievements but also emphasizes the importance of effective science communication in fostering public understanding and appreciation of research.

Deshpande AJ, Cusan M, Rawat VP, Reuter H, Krause A, Pott C, Quintanilla-Martinez L, Kakadia P, Kuchenbauer F, Ahmed F, Delabesse E, Hahn M, Lichter P, Kneba M, Hiddemann W, Macintyre E, Mecucci C, Ludwig WD, Humphries RK, Bohlander SK, Feuring-Buske M, Buske C. Acute myeloid leukemia is propagated by a leukemic stem cell with lymphoid characteristics in a mouse model of CALM/AF10-positive leukemia. Cancer Cell. 2006 Nov;10(5):363-74. doi: 10.1016/j.ccr.2006.08.023. PMID: 17097559.

Deshpande AJ, Deshpande A, Sinha AU, Chen L, Chang J, Cihan A, Fazio M, Chen CW, Zhu N, Koche R, Dzhekieva L, Ibáñez G, Dias S, Banka D, Krivtsov A, Luo M, Roeder RG, Bradner JE, Bernt KM, Armstrong SA. AF10 regulates progressive H3K79 methylation and HOX gene expression in diverse AML subtypes. Cancer Cell. 2014 Dec 8;26(6):896-908. doi: 10.1016/j.ccell.2014.10.009. Epub 2014 Nov 20. PMID: 25464900; PMCID: PMC4291116.

Sinha S, Barbosa K, Cheng K, Leiserson MDM, Jain P, Deshpande A, Wilson DM 3rd, Ryan BM, Luo J, Ronai ZA, Lee JS, Deshpande AJ, Ruppin E. A systematic genome-wide mapping of oncogenic mutation selection during CRISPR-Cas9 genome editing. Nat Commun. 2021 Nov 11;12(1):6512. doi: 10.1038/s41467-021-26788-6. Erratum in: Nat Commun. 2022 May 16;13(1):2828. doi: 10.1038/s41467-022-30475-5. PMID: 34764240; PMCID: PMC8586238.

Targeting COMPASS to Cure Childhood Leukemia (Ali Shilatifard)

The Menin-MLL Complex and Small Molecule Inhibitors (Yadira Soto-Feliciano)

MLL Proteins in Mixed-Lineage Leukemia (Yali Dou)

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In this episode Dr. Raffaele Teperino shares insights from his ongoing research focused on developmental programming, particularly how paternal health before conception influences not only offspring health but also maternal health outcomes. As we trace his academic journey from studying biotechnology and pharmacology to leading his own lab, Dr. Teperino reflects on his early fascination with medicine, the pivotal experiences that shaped his career, and the integration of epigenetics into understanding metabolic diseases.

We discuss the nuances of epigenetics—going beyond simple chromatin biology to examine its wider implications on phenotypic variation. Dr. Teperino emphasizes his approach of modeling relevant physiological phenomena in the lab to better understand the underlying mechanisms driving conditions like obesity and metabolic disruption. A particular focus is placed on his experiences during his postdoctoral years, where he investigated the developmental pathways of hedgehog signaling and its metabolic implications in adipogenesis.

Our talk shifts towards the practical implications of his research, highlighting recent investigations into how circadian rhythms and paternal lifestyles influence offspring health. Dr. Teperino reveals his findings on how disturbances in circadian rhythms can lead to intergenerational health issues, showcasing the surprising effects observed in offspring of fathers experiencing circadian misalignment. We delve into the significance of seminal fluid as a potential medium for intergenerational transfer of stress responses, examining the role of stress hormones and their impacts on fetal development.

As we explore a fascinating recent study highlighting the impact of paternal diets on future generations, Dr. Teperino underscores the importance of understanding the shorter exposure periods sufficient to trigger these health changes. He presents data that links paternal obesity and preconception health to an increased risk of obesity and insulin resistance in children, challenging traditional narratives around maternal responsibility for offspring health.

Darr J, Tomar A, Lassi M, Gerlini R, Berti L, Hering A, Scheid F, Hrabě de Angelis M, Witting M, Teperino R. iTAG-RNA Isolates Cell-Specific Transcriptional Responses to Environmental Stimuli and Identifies an RNA-Based Endocrine Axis. Cell Rep. 2020 Mar 3;30(9):3183-3194.e4. doi: 10.1016/j.celrep.2020.02.020. PMID: 32130917.

Lassi M, Tomar A, Comas-Armangué G, Vogtmann R, Dijkstra DJ, Corujo D, Gerlini R, Darr J, Scheid F, Rozman J, Aguilar-Pimentel A, Koren O, Buschbeck M, Fuchs H, Marschall S, Gailus-Durner V, Hrabe de Angelis M, Plösch T, Gellhaus A, Teperino R. Disruption of paternal circadian rhythm affects metabolic health in male offspring via nongerm cell factors. Sci Adv. 2021 May 26;7(22):eabg6424. doi: 10.1126/sciadv.abg6424. PMID: 34039610; PMCID: PMC8153725.

Tomar A, Gomez-Velazquez M, Gerlini R, Comas-Armangué G, Makharadze L, Kolbe T, Boersma A, Dahlhoff M, Burgstaller JP, Lassi M, Darr J, Toppari J, Virtanen H, Kühnapfel A, Scholz M, Landgraf K, Kiess W, Vogel M, Gailus-Durner V, Fuchs H, Marschall S, Hrabě de Angelis M, Kotaja N, Körner A, Teperino R. Epigenetic inheritance of diet-induced and sperm-borne mitochondrial RNAs. Nature. 2024 Jun;630(8017):720-727. doi: 10.1038/s41586-024-07472-3. Epub 2024 Jun 5. PMID: 38839949; PMCID: PMC11186758.

The Impact of Paternal Diet on Offspring Metabolism (Upasna Sharma)

Transgenerational Inheritance and Evolution of Epimutations (Peter Sarkies)

The Role of Small RNAs in Transgenerational Inheritance in C. elegans (Oded Rechavi)

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In this episode of the Epigenetics Podcast, we talked with Dr. Frank Johannes from the Technical University of Munich in Freising about his work on evolutionary clocks and epigenetic inheritance in plants.

In this episode we discuss Dr. Johannes pursuits in understanding how heritable epigenetic variations, particularly through DNA methylation, affect phenotypic diversity in plants. He shared insights about groundbreaking research initiatives he has led, including one of the first population epigenetic studies in plants that effectively linked heritable DNA methylation changes to critical traits like flowering time and root length. This work underscored the importance of epigenetic factors that extend beyond traditional genetic sequences, illustrating a significant shift in how we comprehend inheritance and trait variation in organisms.

As we dug deeper into the science, we examined Dr. Johannes's innovative approaches to studying chromatin-based mechanisms of genome regulation, allowing for a nuanced understanding of epigenetic inheritance. His lab’s extensive phenotyping of Arabidopsis plants highlighted how inducing heritable variations in DNA methylation could lead to significant trait outcomes – results that have substantial implications for agriculture and understanding complex characteristics across generations.

The dialogue continued to unravel the dynamics between forward and backward epimutations, delving into their heritable nature and their rapid accumulation compared to traditional genetic mutations. Dr. Johannes overturned conventional understanding by presenting epigenetic processes that are not as static as once thought, providing compelling evidence that these spontaneous changes could inform evolutionary clocks; a concept that offers new avenues for studying the relationships between species over relatively short timeframes.

Moreover, we discussed the exciting concept of epigenetic clocks, which play a role in assessing the age of various species, including trees. The potential applications for such clocks in environmental management and the assessment of tree vitality further illuminated the practical impacts of Dr. Johannes's research. These insights also pave the way for sophisticated non-invasive methods of understanding plant biology, which can revolutionize forest management practices in the face of climate change and other ecological pressures.

Colomé-Tatché M, Cortijo S, Wardenaar R, Morgado L, Lahouze B, Sarazin A, Etcheverry M, Martin A, Feng S, Duvernois-Berthet E, Labadie K, Wincker P, Jacobsen SE, Jansen RC, Colot V, Johannes F. Features of the Arabidopsis recombination landscape resulting from the combined loss of sequence variation and DNA methylation. Proc Natl Acad Sci U S A. 2012 Oct 2;109(40):16240-5. doi: 10.1073/pnas.1212955109. Epub 2012 Sep 17. PMID: 22988127; PMCID: PMC3479620.

Cortijo S, Wardenaar R, Colomé-Tatché M, Gilly A, Etcheverry M, Labadie K, Caillieux E, Hospital F, Aury JM, Wincker P, Roudier F, Jansen RC, Colot V, Johannes F. Mapping the epigenetic basis of complex traits. Science. 2014 Mar 7;343(6175):1145-8. doi: 10.1126/science.1248127. Epub 2014 Feb 6. PMID: 24505129.

van der Graaf A, Wardenaar R, Neumann DA, Taudt A, Shaw RG, Jansen RC, Schmitz RJ, Colomé-Tatché M, Johannes F. Rate, spectrum, and evolutionary dynamics of spontaneous epimutations. Proc Natl Acad Sci U S A. 2015 May 26;112(21):6676-81. doi: 10.1073/pnas.1424254112. Epub 2015 May 11. PMID: 25964364; PMCID: PMC4450394.

Yao N, Zhang Z, Yu L, Hazarika R, Yu C, Jang H, Smith LM, Ton J, Liu L, Stachowicz JJ, Reusch TBH, Schmitz RJ, Johannes F. An evolutionary epigenetic clock in plants. Science. 2023 Sep 29;381(6665):1440-1445. doi: 10.1126/science.adh9443. Epub 2023 Sep 28. PMID: 37769069.

Transgenerational Inheritance and Epigenetic Imprinting in Plants (Mary Gehring)

Epigenetic Clocks and Biomarkers of Ageing (Morgan Levine)

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In this episode of the Epigenetics Podcast, we talked with Boyan Bonev from the HelmholtzZetrum in Munich about his work on neuroepigenetics, focusing on gene regulation, chromatin architecture, and primate epigenome evolution,

This Episode focuses on Dr. Bonev’s recent research, particularly focusing on how chromatin architecture and gene regulation influence neural cell identity and function. He discusses his work investigating transcriptional activity in relation to chromatin insulation, highlighting a critical finding that induced expression of genes does not necessarily lead to chromatin insulation—a point that complicates prior assumptions about the relationship between gene expression and chromatin organization. This study aimed to determine the causal versus correlative aspects of chromatin architecture in brain development and links it to developmental processes and neurodevelopmental disorders.

Building on his findings in gene regulation, Dr. Bonev elaborates on a significant study he conducted in his own lab, where he mapped the regulatory landscape of neural differentiation in the mouse neocortex. Here, he employed cutting-edge single-cell sequencing methodologies to analyze intricate gene and enhancer interactions, revealing that selective enhancer-promoter interactions are primarily cell-type specific. This nuanced understanding aids in deciphering the complexities associated with gene expression as it relates to neural stem cells and differentiated neurons, emphasizing the importance of single-cell analyses over bulk sequencing methods.

Moreover, Dr. Bonev reveals a novel methodology developed in his lab that allows for the simultaneous assessment of spatial genome organization, chromatin accessibility, and DNA methylation at high resolution. This advancement not only reduces costs but also enhances the potential to correlate higher-dimensional genomic data with specific biological questions, fostering a more integrative approach to understanding genetic regulation.

The discussion then shifts focus towards Dr. Bonev's recent project profiling primate epigenome evolution, where he investigated the 3D genome organization, chromatin accessibility, and gene expression among iPSCs and neural stem cells from various species, including humans, chimpanzees, gorillas, and macaques. In this research, he identifies trends related to transcription factor evolution and chromatin modifications across species. The insights gleaned from this work underscore the evolutionary significance of structural variations in the 3D genome, pointing to a possible link between chromatin dynamics and the evolutionary development of the primate brain.

Bonev B, Mendelson Cohen N, Szabo Q, Fritsch L, Papadopoulos GL, Lubling Y, Xu X, Lv X, Hugnot JP, Tanay A, Cavalli G. Multiscale 3D Genome Rewiring during Mouse Neural Development. Cell. 2017 Oct 19;171(3):557-572.e24. doi: https://doi.org/10.1016/j.cell.2017.09.043. PMID: 29053968; PMCID: PMC5651218.

Noack, F., Vangelisti, S., Raffl, G. et al. Multimodal profiling of the transcriptional regulatory landscape of the developing mouse cortex identifies Neurog2 as a key epigenome remodeler. Nat Neurosci 25, 154–167 (2022). https://doi.org/10.1038/s41593-021-01002-4

Noack F, Vangelisti S, Ditzer N, Chong F, Albert M, Bonev B. Joint epigenome profiling reveals cell-type-specific gene regulatory programmes in human cortical organoids. Nat Cell Biol. 2023 Dec;25(12):1873-1883. doi: 10.1038/s41556-023-01296-5. Epub 2023 Nov 23. PMID: 37996647; PMCID: PMC10709149.

Characterization of Epigenetic States in the Oligodendrocyte Lineage (Gonçalo Castelo-Branco)

Polycomb Proteins, Gene Regulation, and Genome Organization in Drosophila (Giacomo Cavalli)

The Effect of lncRNAs on Chromatin and Gene Regulation (John Rinn)

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Dr. Stefan Dillinger on LinkedIn

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Email: [email protected]