Epigenetics Podcast

In this episode we speak with Alon Goren from UC San Diego about his work at the intersection of genomic technology development and chromatin biology. We discuss how his lab studies how the epigenome is regulated, how disruption of that regulation contributes to disease, and how technology can be improved to make results more robust and reproducible.

We talk about his early interest in biology, how that developed through medical research training, and how a molecular biology lab shaped the direction of his career. He explains how curiosity about how cells and organisms work led him toward genomics and chromatin research.

We then discuss several methods from his career, including early direct sequencing approaches for small amounts of DNA and RNA, ChIP-based methods for chromatin regulators, and work on improving ChIP-seq workflows. He explains why antibody choice matters, why monoclonal antibodies can improve reproducibility, and how automation helped scale the process.

We also cover his work on spike-in normalization, including the risks of using exogenous chromatin incorrectly and the need for better safeguards in genome-wide comparisons. He describes a newer approach that uses two spike-ins to provide multiple checks on normalization.

Finally, we discuss his work on short tandem repeats, zebrafish heart regeneration, and SIRT6-related polymerase pausing, as well as a newer platform that converts molecular interactions into sequencing-readable barcodes. He closes by stressing the importance of validation, careful protocol design, and methods that can be used reliably by multiple people.

References

Ram, O., Goren, A., Amit, I., Shoresh, N., Yosef, N., Ernst, J., Kellis, M., Gymrek, M., Issner, R., Coyne, M., Durham, T., Zhang, X., Donaghey, J., Epstein, C. B., Regev, A., & Bernstein, B. E. (2011). Combinatorial patterning of chromatin regulators uncovered by genome-wide location analysis in human cells. Cell, 147(7), 1628–1639. https://doi.org/10.1016/j.cell.2011.09.057

Busby, M., Xue, C., Li, C., Farjoun, Y., Gienger, E., Yofe, I., Gladden, A., Epstein, C. B., Cornett, E. M., Rothbart, S. B., Nusbaum, C., & Goren, A. (2016). Systematic comparison of monoclonal versus polyclonal antibodies for mapping histone modifications by ChIP-seq. Epigenetics & chromatin, 9, 49. https://doi.org/10.1186/s13072-016-0100-6

Patel, L. A., Cao, Y., Mendenhall, E. M., Benner, C., & Goren, A. (2024). The Wild West of spike-in normalization. Nature biotechnology, 42(9), 1343–1349. https://doi.org/10.1038/s41587-024-02377-y

Ben-Yair, R., Butty, V. L., Busby, M., Qiu, Y., Levine, S. S., Goren, A., Boyer, L. A., Burns, C. G., & Burns, C. E. (2019). H3K27me3-mediated silencing of structural genes is required for zebrafish heart regeneration. Development (Cambridge, England), 146(19), dev178632. https://doi.org/10.1242/dev.178632

Patel, L., Cao, Y., Xu, T., Modolo, E., Dishon, T., Zhang, L., Mendenhall, E., Heinz, S., Simon, I., Benner, C., & Goren, A. (2025). Improved spike-in normalization clarifies the relationship between active histone modifications and transcription. Genomics. https://doi.org/10.1101/2025.11.25.690627

Xu, T., Wang, J., Shin, Y., Cao, Y., Zhang, L., Modolo, E., Dishon, T., Fisher, J., Norton, M., Fry, C. J., Farjoun, Y., Mendenhall, E., Heinz, S., Benner, C., & Goren, A. (2026). Multiplexed measurements of protein-protein interactions and protein abundance across cellular conditions using Prod&PQ-seq. Genomics. https://doi.org/10.64898/2026.01.01.697286

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In this episode of the Epigenetics Podcast, we talked with Tomohisa Toda from the Max-Planck-Zentrum für Physik und Medizin about his work on the long-term maintenance of neuronal identity, with a focus on epigenetic and RNA-based mechanisms in brain stability and aging.

Dr. Toda describes how brain circuits are stabilized over time, why critical periods are temporally restricted, and how epigenetic regulation may help maintain established neural identity. This led him to postdoctoral work on neural stem cells and long-term maintenance.

We cover his work on nuclear pore and nuclear lamina proteins, including NUP153 and Lamin B1. He explains that NUP153 is enriched in neural stem cells and appears to act as a platform for recruiting factors that help maintain the stem cell epigenome. For Lamin B1, we discuss its decline during aging, how its loss can lead to stem cell exhaustion, reduced adult neurogenesis, and age-related mood dysregulation in the hippocampus.

We also discuss LINE-1 RNA, where we learn that reducing LINE-1 promotes neural progenitor differentiation. He explains that this effect is linked to the RNA sequence itself rather than retrotransposition, based on rescue experiments.

Finally, we talk about his finding that a subset of postnatally born brain cells contains nuclear RNAs that remain detectable for up to two years. He describes their nuclear enrichment, possible association with heterochromatin, and ongoing work to understand their sequence features, modifications, and biological function.

References

Bedrosian, T. A., Houtman, J., Eguiguren, J. S., Ghassemzadeh, S., Rund, N., Novaresi, N. M., Hu, L., Parylak, S. L., Denli, A. M., Randolph-Moore, L., Namba, T., Gage, F. H., & Toda, T. (2021). Lamin B1 decline underlies age-related loss of adult hippocampal neurogenesis. The EMBO journal, 40(3), e105819. https://doi.org/10.15252/embj.2020105819

Zocher, S., McCloskey, A., Karasinsky, A., Schulte, R., Friedrich, U., Lesche, M., Rund, N., Gage, F. H., Hetzer, M. W., & Toda, T. (2024). Lifelong persistence of nuclear RNAs in the mouse brain. Science (New York, N.Y.), 384(6691), 53–59. https://doi.org/10.1126/science.adf3481

Zhilina, D., Bolaños Castro, L. A., Eguiguren, J. S., Zocher, S., Karasinsky, A., Widmer, D., Espinós, A., Borrell, V., Brand, M., Miura, K., Zierau, O., Yun, M. H., & Toda, T. (2026). Dynamic expression of lamin B1 during adult neurogenesis in the vertebrate brain. Developmental dynamics : an official publication of the American Association of Anatomists, 255(2), 187–208. https://doi.org/10.1002/dvdy.70023

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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.

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In this episode of the Epigenetics Podcast, we talked with Peter Becker from the  Biomedical Center Munich about his successful career in Epigenetics, where he discovered the chromatin remodeler ISWI and dosage compensation complex MOF.

Dr. Becker shares thoughts about his postdoctoral work with Carl Wu, where he developed embryo extract systems for studying chromatin assembly and transcription. He explains how work on Drosophila extracts led to the purification of ATP-dependent remodeling factors, including ISWI-related complexes, and how these studies showed that such factors slide nucleosomes and help organize chromatin.

We also cover his move to EMBL and later to Munich, where his lab expanded into dosage compensation in Drosophila. He describes work on the MSL complex targeting, MRE sequences, ROX RNA, DNA shape features, and how biochemical reconstitution was used to study how the complex recognizes the X chromosome.

Finally, we discuss his later work on TIP-60 and histone acetylation, including acetylome studies, and his reflections on leadership roles at EMBL and on the use of the term epigenetics. He emphasizes that epigenetics should be understood as one layer among genetics, environment, and socialization, not as a replacement for genetics.

References

Tsukiyama, T., Becker, P. B., & Wu, C. (1994). ATP-dependent nucleosome disruption at a heat-shock promoter mediated by binding of GAGA transcription factor. Nature, 367(6463), 525–532. https://doi.org/10.1038/367525a0

Varga-Weisz, P. D., Wilm, M., Bonte, E., Dumas, K., Mann, M., & Becker, P. B. (1997). Chromatin-remodelling factor CHRAC contains the ATPases ISWI and topoisomerase II. Nature, 388(6642), 598–602. https://doi.org/10.1038/41587

Corona, D. F., Längst, G., Clapier, C. R., Bonte, E. J., Ferrari, S., Tamkun, J. W., & Becker, P. B. (1999). ISWI is an ATP-dependent nucleosome remodeling factor. Molecular cell, 3(2), 239–245. https://doi.org/10.1016/s1097-2765(00)80314-7

Akhtar, A., & Becker, P. B. (2000). Activation of transcription through histone H4 acetylation by MOF, an acetyltransferase essential for dosage compensation in Drosophila. Molecular cell, 5(2), 367–375. https://doi.org/10.1016/s1097-2765(00)80431-1

Akhtar, A., Zink, D., & Becker, P. B. (2000). Chromodomains are protein-RNA interaction modules. Nature, 407(6802), 405–409. https://doi.org/10.1038/35030169

Villa, R., Schauer, T., Smialowski, P., Straub, T., & Becker, P. B. (2016). PionX sites mark the X chromosome for dosage compensation. Nature, 537(7619), 244–248. https://doi.org/10.1038/nature19338

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In this episode of the Epigenetics Podcast, we talked with Filippo Rijli from the Friedrich Miescher Institute about his work on transcriptional and epigenetic regulation of craniofacial and neuronal development.

Dr. Rijli recalls pivotal moments in his career, including his postdoctoral work where he explored the functions of HoxA2 in craniofacial development. We discuss key findings from his landmark papers, highlighting how individual transcription factors like HoxA2 can dictate the topographic organization of neuronal circuits. His exploration of the whisker-to-barrel cortex circuit in mice unveils how sensory inputs are mapped and processed through precise neuronal connections. This intricate mapping reveals how singular genes can impact the wiring of entire neurological systems.

We also reflect on the evolution of scientific communication throughout Filippo’s career, from the reliance on faxes and handwritten requests for paper reprints to today's instant access to research through digital platforms. His early experiences have instilled in him a resourcefulness that continues to inform his approach to research, particularly in environments with limited resources where collaboration becomes essential.

Our discussion shifts to his recent research endeavors that delve into transcriptional and epigenetic regulation during neuronal and craniofacial development. Dr. Rijli elaborates on a 2015 study which demonstrated how the ectopic expression of HoxA2 could lead to the creation of artificial whisker maps in the brain, providing insights into how transcription factors guide neuronal behavior and circuit formation. His work on the histone methyltransferase EZH2 reveals its crucial role in the tangential migration of cerebellar neurons and the mechanisms that ensure these neurons reach their accurate destinations during development.

Dr. Rijli's research further investigates the chromatin landscape of cranial neural crest cells, uncovering how polycomb group proteins maintain a poised state that enables these cells to respond flexibly to environmental signals. This concept of plasticity is particularly relevant in his latest research on nasal chondrocytes, suggesting that these cells retain developmental potential that may be harnessed in regenerative medicine. The discussions hint at a future where understanding these intricate mechanisms could lead to groundbreaking advancements in treating injuries or diseases.

Throughout the episode, Dr. Rijli’s enthusiasm for discovery is palpable as he shares how each research finding leads to more questions, showcasing the iterative nature of scientific research. This dialogue provides not only a deep dive into his specific studies but also a broader view of how developmental biology continues to evolve, emphasizing the importance of understanding the molecular underpinnings of cellular identity and connectivity.

References

Oury, F., Murakami, Y., Renaud, J. S., Pasqualetti, M., Charnay, P., Ren, S. Y., & Rijli, F. M. (2006). Hoxa2- and rhombomere-dependent development of the mouse facial somatosensory map. Science (New York, N.Y.), 313(5792), 1408–1413. https://doi.org/10.1126/science.1130042

Di Meglio, T., Kratochwil, C. F., Vilain, N., Loche, A., Vitobello, A., Yonehara, K., Hrycaj, S. M., Roska, B., Peters, A. H., Eichmann, A., Wellik, D., Ducret, S., & Rijli, F. M. (2013). Ezh2 orchestrates topographic migration and connectivity of mouse precerebellar neurons. Science (New York, N.Y.), 339(6116), 204–207. https://doi.org/10.1126/science.1229326

Minoux, M., Holwerda, S., Vitobello, A., Kitazawa, T., Kohler, H., Stadler, M. B., & Rijli, F. M. (2017). Gene bivalency at Polycomb domains regulates cranial neural crest positional identity. Science (New York, N.Y.), 355(6332), eaal2913. https://doi.org/10.1126/science.aal2913

Kessler, S., Minoux, M., Joshi, O., Ben Zouari, Y., Ducret, S., Ross, F., Vilain, N., Salvi, A., Wolff, J., Kohler, H., Stadler, M. B., & Rijli, F. M. (2023). A multiple super-enhancer region establishes inter-TAD interactions and controls Hoxa function in cranial neural crest. Nature communications, 14(1), 3242. https://doi.org/10.1038/s41467-023-38953-0

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