Unveiling E2F4,TEAD1 and AP-1 as regulatory transcription factors of the replicative senescence program by multi-omics analysis
作者机构：School of Basic Medical SciencesState Key Laboratory of Natural and Biomimetic DrugsPeking UniversityBeijing 100191China The MOE Key Laboratory of Cell Proliferation and DifferentiationCollege of Life SciencesPeking-Tsinghua Center for Life SciencesPeking UniversityBeijing 100871China State Key Laboratory of Chemical OncogenomicsSchool of Chemical Biology and BiotechnologyPeking University Shenzhen Graduate SchoolShenzhen 518055China
出 版 物：《Protein & Cell》 (蛋白质与细胞（英文版）)
年 卷 期：2022年第13卷第10期
页 面：742-759页
核心收录：
学科分类：0710[理学-生物学] 07[理学] 071008[理学-发育生物学]
基 金：the National Key R&D Program of China(2017YFA0103000,2018YFA0108102) the National Natural Science Foundation of China(31521004,31730059)。
主 题：transcription factor senescence multiomics
摘 要：Senescence,a stable state of growth arrest,affects many physiological and pathophysiological processes,especially aging.Previous work has indicated that transcription factors(TFs)play a role in regulating senescence.However,a systematic study of regulatory TFs during replicative senescence(RS)using multiomics analysis is still lacking.Here,we generated timeresolved RNA-seq,reduced representation bisulfite sequencing(RRBS)and ATAC-seq datasets during RS of mouse skin fibroblasts,which demonstrated that an enhanced inflammatory response and reduced proliferative capacity were the main characteristics of RS in both the transcriptome and epigenome.Through integrative analysis and genetic manipulations,we found that transcription factors E2F4,TEAD1 and AP-1 are key regulators of RS.Overexpression of E2f4 improved cellular proliferative capacity,attenuated SA-β-Gal activity and changed RS-associated differentially methylated sites(DMSs).Moreover,knockdown of Tead1 attenuated SA-β-Gal activity and partially altered the RS-associated transcriptome.In addition,knockdown of Atf3,one member of AP-1 superfamily TFs,reduced Cdkn2a(p16)expression in pre-senescent fibroblasts.Taken together,the results of this study identified transcription factors regulating the senescence program through multi-omics analysis,providing potential therapeutic targets for anti-aging.
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