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A rheostat model for genome organisation and its implications in cancer

Institute of Pathology, University Medical Centre Göttingen, Germany

Monday, March 25th 2019 - 2 p.m. - Auditorium, IGBMC
Hosted by Evi SOUTOGLOU

Spatial organization and gene expression of mammalian chromosomes are maintained and regulated in conjunction with cell cycle progression. This link is perturbed once cells enter senescence. The highly abundant HMGB proteins, known to associate with bent and looped DNA, are actively depleted from senescent cell nuclei to act as extracellular stimuli. Despite their physiological importance, we still lack understanding of the positioning and functional roles of HMGBs on chromatin in vivo. To address this, we mapped their binding genome-wide in different primary cells using a tailored protocol. We then integrated ChIP-seq and Hi-C data with a graph theory approach to uncover HMGB demarcation at the boundaries of particular topologically-associating domains (TADs). These TADs harbor genes involved in key legs of the senescent transcriptional program. Moreover, we used sCLIP and siRNA-mediated knockdown to show that HMGBs are also bona fide RNA-binding proteins affecting splicing choices. Together, our findings highlight a broader than hitherto assumed role for HMGBs in chromatin homeostasis connected to cell cycle potency, and allow us to postulate a “rheostat” model for HMGB function with implications in cancer onset and progression.

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Université de Strasbourg

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