Unveiling E2F4, TEAD1 and AP-1 as regulatory transcription factors of the replicative senescence program by multi-omics analysis.
10.1007/s13238-021-00894-z
- Author:
Yuting WANG
1
;
Liping LIU
1
;
Yifan SONG
2
;
Xiaojie YU
2
;
Hongkui DENG
3
Author Information
1. School of Basic Medical Sciences, State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing, 100191, China.
2. The MOE Key Laboratory of Cell Proliferation and Differentiation, College of Life Sciences, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, 100871, China.
3. School of Basic Medical Sciences, State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing, 100191, China. hongkui_deng@pku.edu.cn.
- Publication Type:Research Support, Non-U.S. Gov't
- Keywords:
multi-omics;
senescence;
transcription factor
- MeSH:
Aging;
Animals;
Cellular Senescence/genetics*;
E2F4 Transcription Factor/genetics*;
Fibroblasts/metabolism*;
Mice;
TEA Domain Transcription Factors/metabolism*;
Transcription Factor AP-1/metabolism*;
Transcriptome
- From:
Protein & Cell
2022;13(10):742-759
- CountryChina
- Language:English
-
Abstract:
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 multi-omics analysis is still lacking. Here, we generated time-resolved 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.
