The PPARγ-SETD8 axis constitutes an epigenetic, p53-independent checkpoint on p21-mediated cellular senescence

Aging Cell
Chieh-Tien ShihBertrand Chin-Ming Tan

Abstract

Cellular senescence is a permanent proliferative arrest triggered by genome instability or aberrant growth stresses, acting as a protective or even tumor-suppressive mechanism. While several key aspects of gene regulation have been known to program this cessation of cell growth, the involvement of the epigenetic regulation has just emerged but remains largely unresolved. Using a systems approach that is based on targeted gene profiling, we uncovered known and novel chromatin modifiers with putative link to the senescent state of the cells. Among these, we identified SETD8 as a new target as well as a key regulator of the cellular senescence signaling. Knockdown of SETD8 triggered senescence induction in proliferative culture, irrespectively of the p53 status of the cells; ectopic expression of this epigenetic writer alleviated the extent doxorubicin-induced cellular senescence. This repressive effect of SETD8 in senescence was mediated by directly maintaining the silencing mark H4K20me1 at the locus of the senescence switch gene p21. Further in support of this regulatory link, depletion of p21 reversed this SETD8-mediated cellular senescence. Additionally, we found that PPARγ acts upstream and regulates SETD8 expression in prol...Continue Reading

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Citations

Jan 31, 2020·Clinical Science·Zhuohao LiuKenneth K Y Cheng
Mar 27, 2019·Current Opinion in Lipidology·Andrea C PostmusJanine K Kruit
Apr 8, 2020·Future Oncology·Sayantani RoychoudhuryNilesh Kumar Sharma
Jan 11, 2020·Frontiers in Oncology·Daniel HeudoblerAlbrecht Reichle
Nov 24, 2020·The International Journal of Biochemistry & Cell Biology·Charles Ducker, Peter E Shaw
Jun 5, 2021·DNA Repair·Ian Hammond-MartelHugo Wurtele
Jul 1, 2021·Toxicology Letters·Ruoman WuChunfeng Lu

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Methods Mentioned

BETA
PCR
flow
ChIP
transfection
reverse transcription PCR
flow cytometry
immunoprecipitation
targeted gene screen

Software Mentioned

UCSC browser
TargetScan
cellquest

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