In this episode of the Epigenetics Podcast, we talked with Iva Tchasovnikarova from the Wellcome Trust Cancer Research UK Gurdon Institute about her work on heterochromatin formation and epigenetic control.

We begin with Dr. Tchasovnikarova's journey into the field of biology, tracing her roots back to her formative years and the pragmatic guidance of her parents. Despite initial uncertainty about her career path, it was her mother’s passion for teaching biology that ultimately inspired her to pursue a degree in the subject.

As Dr. Tchasovnikarova introduces her current role as a group leader at the Gurdon Institute and an assistant professor at the University of Cambridge, she highlights her early work during her PhD which yielded a first-author publication in Science. She reflects on the serendipitous aspects of this experience, detailing a project where she utilised a novel genetic screening system to uncover a repressor complex named HUSH, a pivotal discovery that has implications for understanding transcriptional repression mechanisms in vertebrates.

The conversation progresses into her postdoctoral research, where she further explored the HUSH complex's role alongside another complex, HUSH2. This expansion of her research reveals fascinating insights into how these complexes interact and their potential significance in regulating gene expression, particularly concerning immune responses to viral infections. Dr. Tchasovnikarova outlines her systematic approach to unraveling these complexities, emphasizing the role of reporter systems and genetic screens in uncovering uncharacterized genes and their functions.

In discussing her transition to starting her own lab, Dr. Tchasovnikarova shares her excitement about utilizing methods she developed during her postdoc to discover new regulatory mechanisms. She describes specific experiments that have led to groundbreaking findings, including the characterization of CRAMP1, a regulator of linker histones, which plays a crucial role in the function of the polycomb repressive complex. The intricate relationships between these elements underscore her commitment to understanding the nuances of epigenetic regulation and genome stability.

• Tchasovnikarova, I. A., Timms, R. T., Matheson, N. J., Wals, K., Antrobus, R., Göttgens, B., Dougan, G., Dawson, M. A., & Lehner, P. J. (2015). GENE SILENCING. Epigenetic silencing by the HUSH complex mediates position-effect variegation in human cells. Science (New York, N.Y.), 348(6242), 1481–1485. https://doi.org/10.1126/science.aaa7227
• Danac, J. M. C., Matthews, R. E., Gungi, A., Qin, C., Parsons, H., Antrobus, R., Timms, R. T., & Tchasovnikarova, I. A. (2024). Competition between two HUSH complexes orchestrates the immune response to retroelement invasion. Molecular cell, 84(15), 2870–2881.e5. https://doi.org/10.1016/j.molcel.2024.06.020

• Heterochromatin Protein 1 and its Influence on the Structure of Chromatin (Serena Sanulli)
• Heterochromatin and Phase Separation (Gary Karpen)
• Polycomb and Three-Dimensional Genome Organisation (Oliver Bell)

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In this episode of the Epigenetics Podcast, we talked with Eva Nogales from UC Berkeley about her work on Cryo-EM and the Dynamics of TFIID and PRC2.

We explore the origins of Dr. Nogales's fascination with biology and how her academic journey shifted from physics into the realms of biophysics and structural biology. She shares the profound impact of her training under physicists who instilled a rigorous, quantitative approach to problem-solving, a perspective that continues to influence her work. The importance of visualization emerges as a central theme, showcasing how critical imagery can foster understanding even amidst complex biological structures.

A particular focus of our discussion centers on the transcription factor complex TFIID, a significant milestone in Dr. Nogales's career. She recalls the challenging journey to uncovering its structure for the first time, which involved navigating numerous technical hurdles. Dr. Nogales details how their innovative approaches led to insights about the conformational flexibility and functional dynamics of TFIID, especially in relation to its interactions with DNA during transcription initiation. The richness of this narrative reflects both the perseverance required in scientific discovery and the serendipity that often accompanies groundbreaking breakthroughs.

Transitioning into the epigenetics realm, Dr. Nogales elucidates the critical role of PRC2 in gene silencing and cellular identity preservation. With a focus on chromatin and nucleosome interactions, we unpack the intricate mechanisms by which PRC2 functions in the context of chromatin remodeling and gene regulation. Dr. Nogales recounts how collaborations and the imaginative contributions of her lab members led to novel research trajectories, particularly the elucidation of structural states of PRC2 bound to chromatin and characterized by novel methodologies developed within her lab.

Further, our discussion touches on Dr. Nogales’s recent findings regarding the nuanced interplay of various cofactors involved in PRC2's regulatory functions. We delve into her exciting projects aiming to bring further clarity to the complex dynamics of chromatin interaction and the distinct forms of PRC2. Dr. Nogales's unyielding commitment to research is mirrored in her ambition to explore unresolved questions surrounding these multifaceted biological processes.

• Andel F 3rd, Ladurner AG, Inouye C, Tjian R, Nogales E. Three-dimensional structure of the human TFIID-IIA-IIB complex. Science. 1999 Dec 10;286(5447):2153-6. doi: 10.1126/science.286.5447.2153. PMID: 10591646.
• Cianfrocco MA, Kassavetis GA, Grob P, Fang J, Juven-Gershon T, Kadonaga JT, Nogales E. Human TFIID binds to core promoter DNA in a reorganized structural state. Cell. 2013 Jan 17;152(1-2):120-31. doi: 10.1016/j.cell.2012.12.005. PMID: 23332750; PMCID: PMC3552382.
• Yang Z, Mameri A, Cattoglio C, Lachance C, Florez Ariza AJ, Luo J, Humbert J, Sudarshan D, Banerjea A, Galloy M, Fradet-Turcotte A, Lambert JP, Ranish JA, Côté J, Nogales E. Structural insights into the human NuA4/TIP60 acetyltransferase and chromatin remodeling complex. Science. 2024 Aug 23;385(6711):eadl5816. doi: 10.1126/science.adl5816. Epub 2024 Aug 23. PMID: 39088653.

• Structural Analysis of Nucleosomes During Transcription (Lucas Farnung)
• Molecular Mechanisms of Chromatin Modifying Enzymes (Karim-Jean Armache)
• From Nucleosome Structure to Function (Karolin Luger)

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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.

• 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.

• The Effect of lncRNAs on Chromatin and Gene Regulation (John Rinn)
• The Role of lncRNAs in Tumor Growth and Treatment (Sarah Diermeier)
• The Role of Small RNAs in Transgenerational Inheritance in C. elegans (Oded Rechavi)

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