4D Genome Rewiring during Oncogene-Induced and Replicative Senescence

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Sati, Satish | Bonev, Boyan | Szabo, Quentin | Jost, Daniel | Bensadoun, Paul | Serra, Francois | Loubiere, Vincent | Papadopoulos, Giorgio Lucio | Rivera-Mulia, Juan-Carlos | Fritsch, Lauriane | Bouret, Pauline | Castillo, David | Gelpi, Josep Ll. | Orozco, Modesto | Vaillant, Cedric | Pellestor, Franck | Bantignies, Frederic | Marti-Renom, Marc | Gilbert, David, M | Lemaitre, Jean-Marc | Cavalli, Giacomo

Edité par CCSD ; Cell Press -

International audience. To understand the role of the extensive senescence-associated 3D genome reorganization, we generated genome-wide chromatin interaction maps, epigenome, replication-timing, whole-genome bisulfite sequencing, and gene expression profiles from cells entering replicative senescence (RS) or upon oncogene-induced senescence (OIS). We identify senescence-associated heterochromatin domains (SAHDs). Differential intra- versus inter-SAHD interactions lead to the formation of senescence-associated heterochromatin foci (SAHFs) in OIS but not in RS. This OIS-specific configuration brings active genes located in genomic regions adjacent to SAHDs in close spatial proximity and favors their expression. We also identify DNMT1 as a factor that induces SAHFs by promoting HMGA2 expression. Upon DNMT1 depletion, OIS cells transition to a 3D genome conformation akin to that of cells in replicative senescence. These data show how multi-omics and imaging can identify critical features of RS and OIS and discover determinants of acute senescence and SAHF formation.

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