Open AccessAP-1 imprints a reversible transcriptional programme of senescent cells
Author(s) -
Ricardo Iván Martínez-Zamudio,
Pierre-François Roux,
José Américo N L F de Freitas,
Lucas Robinson,
Gregory J. Dore,
Bin Sun,
Dimitri Belenki,
Maja Milanovic,
Utz Herbig,
Clemens A. Schmitt,
Jesús Gil,
Oliver Bischof
Publication year - 2020
Publication title -
nature cell biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 11.38
H-Index - 369
eISSN - 1476-4679
pISSN - 1465-7392
DOI - 10.1038/s41556-020-0529-5
Subject(s) - senescence , epigenetics , epigenome , biology , transcription factor , enhancer , microbiology and biotechnology , chromatin , transcriptome , phenotype , genetics , gene expression , dna methylation , gene
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.