GSE106146
Histone acetyltransferase p300 induces de novo super-enhancers to drive cellular senescence [ChIP-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: This study compares genome-wide ChIP-seq profiles of several histone post-translational modifications in proliferating and senescent fibroblasts. The PTMs studied include the acetylation marks H3K18ac, H3K23ac, H3K27ac, H3K122ac, H4K5ac, and the methylation mark H3K4me1. Each PTM chIP-seq was done in two replicates in both proliferating and replicative senescent cells. To control for sonication efficiency bias, whole histone subunit H3 and H4 along with input and IgG were sequenced over four replicates in both proliferating and replicative senescent cells. Additionally, chIP-seq for the enhancer decorating histone PTMs H3K4me1 and H3K27ac was also performed in cells undergoing irradiation-induced senescence (IR); this experiment was performed using whole histone subunit H3 along with input and IgG as a control for sonication efficiency, and all samples were sequenced in two replicates. Finally, chIP-seq for histone acetyltransferases CBP and p300 was performed along with a separate input and IgG in proliferating and replicative senescent cells, and all samples were sequenced in two replicates. Please note that several processed data files were generated from multiple samples as indicated in the the correponding sample description field and thus are avilable as Series supplementary file.