Polycomb and Three-Dimensional Genome Organisation (Oliver Bell)

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

Related Episodes

• Effects of DNA Methylation on Chromatin Structure and Transcription (Dirk Schübeler)
• Polycomb Proteins, Gene Regulation, and Genome Organization in Drosophila (Giacomo Cavalli)
• Transcription and Polycomb in Inheritance and Disease (Danny Reinberg)

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