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

Autor:	Sen P; Epigenetics Institute, Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA 19104, USA., Lan Y; Epigenetics Institute, Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA 19104, USA., Li CY; Epigenetics Institute, Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA 19104, USA., Sidoli S; Epigenetics Institute, Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA., Donahue G; Epigenetics Institute, Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA 19104, USA., Dou Z; Epigenetics Institute, Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA 19104, USA., Frederick B; High Throughput Screening Core, Department of Microbiology, University of Pennsylvania, Philadelphia, PA 19104, USA., Chen Q; Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA., Luense LJ; Epigenetics Institute, Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA 19104, USA., Garcia BA; Epigenetics Institute, Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA., Dang W; Huffington Center on Aging, Baylor College of Medicine, Houston, TX 77030, USA., Johnson FB; Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA., Adams PD; Sanford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA; Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1BD, UK., Schultz DC; High Throughput Screening Core, Department of Microbiology, University of Pennsylvania, Philadelphia, PA 19104, USA., Berger SL; Epigenetics Institute, Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Genetics, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Biology, School of Arts and Sciences, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: bergers@pennmedicine.upenn.edu.
Jazyk:	angličtina
Zdroj:	Molecular cell [Mol Cell] 2019 Feb 21; Vol. 73 (4), pp. 684-698.e8. Date of Electronic Publication: 2019 Feb 14.
DOI:	10.1016/j.molcel.2019.01.021
Abstrakt:	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. (Copyright © 2019 Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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