AP-1 imprints a reversible transcriptional programme of senescent cells.

Nature Cell Biology
Ricardo Ivan Martinez ZamudioOliver Bischof

Abstract

Senescent cells affect many physiological and pathophysiological processes. While select genetic and epigenetic elements for senescence induction have been identified, the dynamics, epigenetic mechanisms and regulatory networks defining senescence competence, induction and maintenance remain poorly understood, precluding the deliberate therapeutic targeting of senescence for health benefits. Here, we examined the possibility that the epigenetic state of enhancers determines senescent cell fate. We explored this by generating time-resolved transcriptomes and epigenome profiles during oncogenic RAS-induced senescence and validating central findings in different cell biology and disease models of senescence. Through integrative analysis and functional validation, we reveal links between enhancer chromatin, transcription factor recruitment and senescence competence. We demonstrate that activator protein 1 (AP-1) 'pioneers' the senescence enhancer landscape and defines the organizational principles of the transcription factor network that drives the transcriptional programme of senescent cells. Together, our findings enabled us to manipulate the senescence phenotype with potential therapeutic implications.

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Citations

Jun 28, 2020·Nature Cell Biology·Sara Zumerle, Andrea Alimonti
Dec 10, 2020·Médecine sciences : M/S·Julien Cherfils-Vicini, Éric Gilson
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Dec 18, 2021·Cell Death and Differentiation·Irene Fernández-DuranJuan Carlos Acosta

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Datasets Mentioned

BETA
GM21
GSE98588
GSE134753
GSE134751

Methods Mentioned

BETA
acetylation
ChIP-seq
immunoprecipitation
PCA
footprinting
transfections
transgenic
PCR
Assay
transfection

Software Mentioned

DataAssist
ChromstaR
Zenodo
RAS
GSEA
OIS
limma
ZEN
WGCNA
Cytoscape

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