Oncogene-Induced Senescence Uniquely Alters Genome Architecture

Oncogene-induced senescence (OIS) and replicative senescence (RS) share many characteristics, but the nuclear architecture of cells undergoing OIS is dramatically different from that of cells undergoing RS, with the former being notable for the presence of heterochromatin bodies known as senescence-associated heterochromatin foci (SAHF). In a study of senescence-associated genome reorganization, Sati and colleagues found that the differences in 3D genome organization between cells undergoing OIS and those undergoing RS. Although both cell types exhibited loss of close cis contacts and gain of far cis contacts, cells undergoing RS had reduced genomic compartmentalization, whereas cells undergoing OIS had increased compartmentalization driven mainly by an increase in interactions between heterochromatin domains that formed SAHFs. These SAHFs were formed by chromosomal domains termed senescence-associated heterochromatin domains (SAHD), which were defined by their high levels of histone 3 lysine residue 9 trimethylation, were low in genes. Mechanistically, SAHF formation in cells undergoing OIS appeared to be caused by local decompaction of SAHDs followed by their detachment from the nuclear lamina and weakened inter-SAHD interactions. Loss of DNA (cytosine-5)-methyltransferase 1 (DNMT1) abolished OIS-induced SAHF formation, and OIS-mediated DNMT1 induction led to hypermethylation of BRCA1 and ZNF350 (encoding a zinc-finger protein that interacts with BRCA1), possibly leading to their downregulation. This caused derepression of HMGA2, encoding an enhanceosome component, leading to SAHF formation. SAHF assembly was associated with gene-expression alterations; specifically, although SAHFs were largely heterochromatic, there was upregulation of some SAHF-adjacent genes related to cancer, organismal injury and abnormalities, and inflammatory responses. In total, this work provides a deep, three-dimensional view into the chromatin organization of cells undergoing OIS and includes a mechanistic model explaining the formation of OIS-specific SAHFs.

Sati S, Bonev B, Szabo Q, Jost D, Bensadoun P, Serra F, et al. 4D Genome Rewiring during Oncogene-Induced and Replicative Senescence. Molec Cell 2020 Mar 26 [Epub ahead of print].

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