GSE105951
Histone acetyltransferase p300 induces de novo super-enhancers to drive cellular senescence [RNA-seq]
Cellular senescence is a state of stable proliferative arrest induced by stress and is associated with a pro-inflammatory program. Senescent cells have anti-tumorigenic properties, however, their accumulation during aging contributes to chronic inflammation and age-related diseases. While senescence is associated with profound alterations of the epigenome, a systematic view of epigenetic factors in regulating senescence is lacking. Here, we curated a library of short hairpin RNAs for targeted silencing of all known epigenetic factors and performed a high-throughput loss-of-function screen to identify epigenetic proteins whose downregulation can delay replicative senescence of primary human cells. This screen identified multiple new players regulating senescence, including the histone acetyltransferase p300 that was found to be a primary driver of the senescent phenotype.  p300, but not the paralogous CBP, induces a dynamic hyper-acetylated chromatin state in senescence and promotes the formation of active enhancer elements in the non-coding genome, leading to a senescence-specific gene expression program.  Our work illustrates a causal role of histone acetyltransferases and acetylation in senescence, and suggests p300 as a potential therapeutic target for senescence and age-related diseases. Overall design: Includes two replicates each of proliferating and senescent IMR90 fibroblasts RNA-seq was performed in IMR90 fibroblasts with either an shRNA knockdown of histone acetyltransferase CBP (two replicates) or with a control luciferase vector (one replicate)