Epigenetics Podcast

In this episode of the Epigenetics Podcast, we talked with Michaela Frye from he German Cancer Research Center (DKFZ) in Heidelberg about her work on the role of RNA modifications and RNA binding proteins in gene expression and cancer development.

Central to Dr. Frey’s work is the NSUN family of RNA-modifying proteins, which she first encountered during her postdoctoral research. Initially perceived as a DNA methyltransferase, she unwittingly discovered that this family also plays vital roles in RNA methylation. Her exploration revealed that these proteins significantly affect gene stability and translation processes, especially under stress, making them critical players in cancer pathology.

As her research progressed, Frey transitioned into her own lab, where she continued exploring RNA modifications in the context of skin and cancer cells. She emphasizes the critical distinction between the roles of different RNA modifications in various cellular contexts, especially highlighting the differences between steady-state stem cells and those undergoing differentiation or stress responses. Frey's lab investigates how these modifications regulate translational processes, which are essential for cellular adaptation to environmental changes.

Frey further discusses her findings related to the NSUN proteins in stem cell function and their implications for germ cell differentiation in testes. This intricate relationship between RNA modifications and cellular dynamics underscores the significance of epitranscriptomics in understanding cancer treatment resistance and cellular adaptation mechanisms.

Recent findings from her team at DKFZ show a compelling connection between mitochondrial function and RNA modifications in cancer cells. Frey articulates a newfound interest in how these modifications influence cellular responses to cancer therapies, particularly how their regulation may mitigate treatment resistance.

Reflecting on the evolution of RNA modification research, she notes that the field has matured rapidly but acknowledges the challenges posed by abundant yet often contradictory findings. Frey advocates for a clearer understanding of the fundamental functions of distinct RNA modifications to harness their potential in therapeutic contexts effectively.

References

Blanco S, Kurowski A, Nichols J, et al. The RNA-methyltransferase Misu (NSun2) poises epidermal stem cells to differentiate. Plos Genetics. 2011 Dec;7(12):e1002403. DOI: 10.1371/journal.pgen.1002403. PMID: 22144916; PMCID: PMC3228827

Hussain S, Tuorto F, Menon S, et al. The mouse cytosine-5 RNA methyltransferase NSun2 is a component of the chromatoid body and required for testis differentiation. Molecular and Cellular Biology. 2013 Apr;33(8):1561-1570. DOI: 10.1128/mcb.01523-12. PMID: 23401851; PMCID: PMC3624257

Blanco S, Bandiera R, Popis M, et al. Stem cell function and stress response are controlled by protein synthesis. Nature. 2016 Jun;534(7607):335-340. DOI: 10.1038/nature18282. PMID: 27306184; PMCID: PMC5040503

Delaunay S, Pascual G, Feng B, et al. Mitochondrial RNA modifications shape metabolic plasticity in metastasis. Nature. 2022 Jul;607(7919):593-603. DOI: 10.1038/s41586-022-04898-5. PMID: 35768510; PMCID: PMC9300468.

Related Episodes

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

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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 Oliver Bell from the University of Southern California in Los Angeles about his work on chromatin-based regulatory systems that encode cellular memory and their implications for development and disease.

The Interview starts with Dr. Bell describing his early career contributions to understanding the functionality of histone methylation in facilitating dosage compensation and gene silencing. His efforts at dissecting the complexities of epigenetic regulation culminate in significant discoveries that highlight the nuanced effects of chromatin adjustments on gene activity and stability across cell divisions.

As we progress, Dr. Bell shares details about his postdoctoral research, where he engineered systems to study chromatin remodeling and the maintenance of transcriptional states through development. His innovative use of induced proximity to manipulate chromatin modifiers offers groundbreaking approaches to understanding how epigenetic states can be established and sustained, alongside the implications for therapeutic strategies in cancer treatment.

An important aspect of our discussion centers on his identification of the ZFP462 protein, which plays a critical role in neurodevelopmental disorders. Dr. Bell outlines his lab's ongoing research into deciphering how this zinc finger protein interacts with enhancers to influence gene regulation in embryonic stem cells and its potential connection to specific diseases. This leads to an engaging dialogue about the relationship between 3D genome organization and epigenetic regulation, focusing on how disruptions in chromatin architecture may affect gene expression.

Towards the end of our conversation, we touch upon the emerging potential of AI in epigenetic research, exploring how advances in technology could facilitate the screening of small molecules targeted at chromatin-modifying complexes. Dr. Bell offers a forward-looking perspective on the future applications of this research, revealing his aspirations for therapeutic developments based on his findings.

References

Bell, O., Wirbelauer, C., Hild, M., Scharf, A. N., Schwaiger, M., MacAlpine, D. M., Zilbermann, F., van Leeuwen, F., Bell, S. P., Imhof, A., Garza, D., Peters, A. H., & Schübeler, D. (2007). Localized H3K36 methylation states define histone H4K16 acetylation during transcriptional elongation in Drosophila. The EMBO journal, 26(24), 4974–4984. https://doi.org/10.1038/sj.emboj.7601926

Hathaway, N. A., Bell, O., Hodges, C., Miller, E. L., Neel, D. S., & Crabtree, G. R. (2012). Dynamics and memory of heterochromatin in living cells. Cell, 149(7), 1447–1460. https://doi.org/10.1016/j.cell.2012.03.052

Moussa, H. F., Bsteh, D., Yelagandula, R., Pribitzer, C., Stecher, K., Bartalska, K., Michetti, L., Wang, J., Zepeda-Martinez, J. A., Elling, U., Stuckey, J. I., James, L. I., Frye, S. V., & Bell, O. (2019). Canonical PRC1 controls sequence-independent propagation of Polycomb-mediated gene silencing. Nature communications, 10(1), 1931. https://doi.org/10.1038/s41467-019-09628-6

Yelagandula, R., Stecher, K., Novatchkova, M. et al. ZFP462 safeguards neural lineage specification by targeting G9A/GLP-mediated heterochromatin to silence enhancers. Nat Cell Biol 25, 42–55 (2023). https://doi.org/10.1038/s41556-022-01051-2

Bsteh, D., Moussa, H.F., Michlits, G. et al. Loss of cohesin regulator PDS5A reveals repressive role of Polycomb loops. Nat Commun 14, 8160 (2023). https://doi.org/10.1038/s41467-023-43869-w

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Effects of DNA Methylation on Chromatin Structure and Transcription (Dirk Schübeler)

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Transcription and Polycomb in Inheritance and Disease (Danny Reinberg)

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In this episode of the Epigenetics Podcast, we talked with Patrick Murphy from Cornell University about his work on gene regulation and cellular identity.

Dr. Murphy's research focuses on the molecular mechanisms that govern gene expression through transcriptional and chromatin-based regulatory networks. At the start of the Interview Dr. Murphy describes an innovative single-molecule analytical approach he developed during his early research. This method enables the simultaneous detection of multiple epigenetic marks and contributes to his foundational studies on chromatin biology. Focusing on chromatin states, he introduces the concept of placeholder nucleosomes which are specialised nucleosomes that play key roles in maintaining a permissive chromatin state and facilitating gene activation during embryonic development.

The discussion further explores Dr. Murphy's transition from studying Drosophila to working with zebrafish, highlighting his focus on chromatin reprogramming during zygotic genome activation. He presents data from his collaborations that reveal intriguing roles for specific chromatin marks, emphasising how these discoveries hold potential for understanding gene expression regulation in both zebrafish and mammalian models.

Dr. Murphy also shares insights into a project investigating the impacts of paternal cigarette smoke on offspring health, which led to an exploration of systemic inflammation responses and their lasting effects on gene expression in the brain. This unique intersection of basic and translational research underlines the wide-ranging implications of his findings.

References

Murphy, P. J., Cipriany, B. R., Wallin, C. B., Ju, C. Y., Szeto, K., Hagarman, J. A., Benitez, J. J., Craighead, H. G., & Soloway, P. D. (2013). Single-molecule analysis of combinatorial epigenomic states in normal and tumor cells. Proceedings of the National Academy of Sciences of the United States of America, 110(19), 7772–7777. https://doi.org/10.1073/pnas.1218495110

Murphy, P. J., Wu, S. F., James, C. R., Wike, C. L., & Cairns, B. R. (2018). Placeholder Nucleosomes Underlie Germline-to-Embryo DNA Methylation Reprogramming. Cell, 172(5), 993–1006.e13. https://doi.org/10.1016/j.cell.2018.01.022

Park, B. J., Hua, S., Casler, K. D., Cefaloni, E., Ayers, M. C., Lake, R. F., Murphy, K. E., Vertino, P. M., O'Connell, M. R., & Murphy, P. J. (2025). CUT&Tag overcomes biases of ChIP and establishes chromatin patterns for repetitive genomic loci. iScience, 28(11), 113757. https://doi.org/10.1016/j.isci.2025.113757

Related Episodes

Pioneer Transcription Factors and Their Influence on Chromatin Structure (Ken Zaret)

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In this episode of the Epigenetics Podcast, we talked with Srinjan Basu from Imperial College London to talk about his work on how chromatin architecture and epigenetic mechanisms orchestrate developmental gene expression programs.

We begin by exploring Dr. Basu's early work at Harvard which involved pioneering Raman-based label-free imaging, allowing the study of chromatin dynamics in live tissue. Here, he tackles technical challenges faced in visualizing DNA interactions, emphasizing the shift from 2D to 3D analysis and the importance of real-time observation of chromatin behavior under various conditions. This segues into his groundbreaking research on single transcription factors interacting with chromatin, revealing subtle but significant changes in the dynamics of gene regulation.

We transition into the complexities of chromatin architecture as Dr. Basu recounts his efforts in mapping the entire mouse genome in single pluripotent cells, unearthing unexpected heterogeneity among cells. This heterogeneity raises intriguing questions about its impact on cellular function, prompting ongoing investigations into chromatin dynamics and the role of remodeling complexes like NuRD in cell fate transitions.

Dr. Basu elucidates how recent studies have begun to bridge the gaps in understanding how transcription factors and chromatin dynamics interact during cellular decisions, particularly emphasizing the influence of mechanical signals and the intrinsic properties of cells. His research underscores the idea that stem cells undergo a preparatory phase for differentiation, highlighting the critical balance of intrinsic and extrinsic factors that govern genetic expression and cellular outcomes.

We also talk about Dr. Basu's current research trajectory, focusing on enhancing imaging techniques to study gene dynamics in tissue contexts relevant to developmental biology and disease states. He illustrates a vision for future projects that integrate advanced imaging tools to investigate transcription factor dynamics and chromatin interactions in live cells and embryos, furthering the understanding of decision-making processes in cellular contexts.

References

Stevens TJ, Lando D, Basu S, et al. 3D structures of individual mammalian genomes studied by single-cell Hi-C. Nature. 2017 Apr;544(7648):59-64. DOI: 10.1038/nature21429. PMID: 28289288; PMCID: PMC5385134.

Basu S, Needham LM, Lando D, et al. FRET-enhanced photostability allows improved single-molecule tracking of proteins and protein complexes in live mammalian cells. Nature Communications. 2018 Jun;9(1):2520. DOI: 10.1038/s41467-018-04486-0. PMID: 29955052; PMCID: PMC6023872.

Related Episodes

Advanced Optical Imaging in 3D Nuclear Organisation (Lothar Schermelleh)

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In this episode of the Epigenetics Podcast, we talked with Peggy Farnham from the Keck School of Medicine at USC about her work on establishing the ChIP Method in mammalian cells.

In this episode, we dive into the relationship between transcription factors, chromatin dynamics, and gene expression with Professor Peggy Farnham from the Keck School of Medicine at USC. Professor Farnham shares her profound insights into how her groundbreaking research has reshaped our understanding of gene regulation and its implications in cancer. We explore how she has been a pioneer in mapping the genome-wide landscape of regulatory proteins, illuminating the molecular logic behind transcriptional control and its disruption in cancer biology.

The interview starts with her instrumental role in adapting chromatin immunoprecipitation (ChIP) technology from yeast to human cells. Professor Farnham reflects on the technical challenges she faced during this transition, such as the quest for visibility of signals in mammalian systems. Her ability to innovate and troubleshoot challenges led to significant advancements in techniques that allow for the rapid identification of transcription factor binding sites, fundamentally changing the landscape of epigenetic research.

As the discussion progresses, we learn about Professor Farnham's active involvement in the ENCODE project, where she contributed to high-resolution mapping of transcription factors and regulatory elements in human cells. She articulates her appreciation for collaborative efforts in science, highlighting how working within a consortium harnesses the collective expertise of diverse research groups. This collaboration not only bolstered the credibility of the data produced but also propelled the field forward in understanding the complexity of gene regulation.

Through her participation in various projects, such as the Psyc-ENCODE consortium and the Roadmap Epigenome Mapping Consortium, Professor Farnham shares insights into her investigation of epigenetic variations, particularly in relation to complex disorders like schizophrenia. Her findings underscore the nuances of enhancer variability among individuals and the implications for understanding disease mechanisms, thereby advancing our knowledge of genetic regulation and its contributions to diverse biological outcomes.

Moreover, the episode highlights Professor Farnham's reflective understanding of emerging technologies in the field. She discusses the evolution of methods that allow researchers to investigate gene regulation at single-cell resolution, recognizing the significant implications these innovations have for our comprehension of cellular differentiation and the transcriptional landscape.

References

Weinmann AS, Bartley SM, Zhang T, Zhang MQ, Farnham PJ. Use of chromatin immunoprecipitation to clone novel E2F target promoters. Molecular and Cellular Biology. 2001 Oct;21(20):6820-6832. DOI: 10.1128/mcb.21.20.6820-6832.2001. PMID: 11564866; PMCID: PMC99859.

Wells J, Farnham PJ. Characterizing transcription factor binding sites using formaldehyde crosslinking and immunoprecipitation. Methods (San Diego, Calif.). 2002 Jan;26(1):48-56. DOI: 10.1016/s1046-2023(02)00007-5. PMID: 12054904.

Rhie SK, Schreiner S, Witt H, et al. Using 3D epigenomic maps of primary olfactory neuronal cells from living individuals to understand gene regulation. Science Advances. 2018 Dec;4(12):eaav8550. DOI: 10.1126/sciadv.aav8550. PMID: 30555922; PMCID: PMC6292713.

Tak YG, Hung Y, Yao L, et al. Effects on the transcriptome upon deletion of a distal element cannot be predicted by the size of the H3K27Ac peak in human cells. Nucleic Acids Research. 2016 May;44(9):4123-4133. DOI: 10.1093/nar/gkv1530. PMID: 26743005; PMCID: PMC4872074.

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