4D genome rewiring during oncogene-induced and replicative senescence

Sati, Satish; Serra, François; Castillo Andreo, David; Marti-Renom, Marc A.; Cavalli, Giacomo

doi:http://dx.doi.org/10.1016/j.molcel.2020.03.007

4D genome rewiring during oncogene-induced and replicative senescence

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Sati S, Bonev B, Szabo Q, Jost D, Bensadoun P, Serra F et al. V. Mol Cell. 2020 May 7; 78(3): 522-538.e9. DOI: 10.1016/j.molcel.2020.03.007

Abstract

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.