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.
Deep multi-omics characterization of replicative and oncogene-induced senescence
Senescence-associated heterochromatin domains (SAHDs) form SAHFs via 3D changes
DNMT1 is required for SAHF formation via regulation of HMGA2 expression
SAHF formation leads to expression of SAHF-adjacent genes via 3D chromatin contacts
Sati et al. studied 3D chromatin organization in different types of cellular senescence. They have identified DNMT1 and HMGA2-mediated changes in the structural organization of senescence-associated heterochromatin domains (SAHDs) and architecture-associated gene-expression changes as the key difference among different senescent systems.