Histone Acetyltransferase p300 Induces De Novo Super-Enhancers to Drive Cellular Senescence

Mol Cell. 2019 Feb 21;73(4):684-698.e8. doi: 10.1016/j.molcel.2019.01.021. Epub 2019 Feb 14.


Accumulation of senescent cells 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 proteins and performed a high-throughput screen to identify key candidates whose downregulation can delay replicative senescence of primary human cells. This screen identified multiple new players 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 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.

Keywords: chromatin; enhancers; epigenetics; p300; senescence.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation
  • Cell Proliferation* / genetics
  • Cellular Senescence* / genetics
  • Chromatin / enzymology*
  • Chromatin / genetics
  • Chromatin Assembly and Disassembly* / genetics
  • Epigenetic Repression
  • Fibroblasts / enzymology*
  • HEK293 Cells
  • High-Throughput Nucleotide Sequencing / methods
  • Histones / genetics
  • Histones / metabolism*
  • Humans
  • Protein Processing, Post-Translational*
  • RNA Interference
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / metabolism
  • Signal Transduction
  • Time Factors
  • Transcription, Genetic
  • p300-CBP Transcription Factors / genetics
  • p300-CBP Transcription Factors / metabolism*


  • Chromatin
  • Histones
  • RNA, Small Interfering
  • p300-CBP Transcription Factors
  • p300-CBP-associated factor