期刊
MOLECULAR CELL
卷 73, 期 4, 页码 684-+出版社
CELL PRESS
DOI: 10.1016/j.molcel.2019.01.021
关键词
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资金
- NIH [P01AG031862, CA196539, GM110174, AI118891]
- CPRIT [R1306]
- Ted Nash Long Life Foundation
- American Heart Association [15POST21230000]
- AFAR Irene Diamond Transition Award [DIAMOND 17113]
- NATIONAL CANCER INSTITUTE [P01CA196539] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE ON AGING [ZIAAG000679] Funding Source: NIH RePORTER
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.
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