In this episode of the Epigenetics Podcast, we talked with Anders Sejr Hansen from MIT about his work on the impact of 3D genome structures on gene expression, the roles of proteins like CTCF and cohesin, and advanced techniques like Region Capture Micro-C for mapping genome organisation.

Dr. Sejr Hansen introduces his research focusing on the relationship between three-dimensional genome structure and function, specifically how these structures can influence gene expression. He elaborates on the importance of transcription factors and the role of looping structures in gene regulation, emphasizing the implications of his work for understanding gene functionality in the context of both development and disease.

The conversation then shifts to discussing loop extrusion and the factors affecting loop stability, primarily CTCF and cohesin. Dr. Sejr Hansen highlights the dynamics of these proteins' binding interactions and how their speeds challenge the notion of stable looping structures in the genome. With a keen interest in CTCF's role, he explains how the protein interacts with DNA and the mechanistic aspects of transcription factor movement, alluding to research findings that reveal that CTCF and cohesin tend to form clusters which may play vital roles in establishing chromatin structure. As the interview progresses, Dr. Sejr Hansen details his transition to leading his own lab at MIT, emphasizing the continuation of his earlier work while expanding into new methodologies for studying chromatin. He underscores the importance of understanding not just the static structures of DNA interactions, but the dynamic nature of these relationships and how they influence gene expression. His lab's recent focus has included using advanced imaging techniques to assess the dynamics of chromatin interactions more precisely.

The discussion then touches on specific findings from Dr. Sejr Hansen's lab regarding the relationship between genome organization and double-strand break repair mechanisms. He emphasizes how the repair machinery can affect chromatin structure and underscores the essential role of cohesin in facilitating effective double-strand break repair by keeping broken DNA ends in proximity. He suggests that loop extrusion might help prevent genetic material from diffusing too far apart and improve the efficiency of repair.

Dr. Sejr Hansen also discusses innovations in genome mapping techniques, particularly the development of Region Capture Micro-C, which facilitates deeper insights into the three-dimensional organization of the genome. This method allows researchers to achieve significantly higher resolution in their analyses compared to traditional 3D genomics techniques like Hi-C. He outlines the technical process and the implications of their findings, especially regarding enhancer-promoter interactions and the surprisingly promiscuous nature of these relationships.

Anders S Hansen, Iryna Pustova, Claudia Cattoglio, Robert Tjian, Xavier Darzacq (2017) CTCF and cohesin regulate chromatin loop stability with distinct dynamics eLife 6:e25776 https://doi.org/10.7554/eLife.25776

Claudia Cattoglio, Iryna Pustova, Nike Walther, Jaclyn J Ho, Merle Hantsche-Grininger, Carla J Inouye, M Julius Hossain, Gina M Dailey, Jan Ellenberg, Xavier Darzacq, Robert Tjian, Anders S Hansen (2019) Determining cellular CTCF and cohesin abundances to constrain 3D genome models eLife 8:e40164 https://doi.org/10.7554/eLife.40164

Goel, V.Y., Huseyin, M.K. & Hansen, A.S. Region Capture Micro-C reveals coalescence of enhancers and promoters into nested microcompartments. Nat Genet 55, 1048–1056 (2023). https://doi.org/10.1038/s41588-023-01391-1

Biophysical Modeling of 3-D Genome Organization (Leonid Mirny)

Unraveling Mechanisms of Chromosome Formation (Job Dekker)

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