AP-1 imprints a reversible transcriptional programme of senescent cells

Autor: Dimitri Belenki, José Américo N L F de Freitas, Utz Herbig, Maja Milanovic, Oliver Bischof, Jesús Gil, Pierre-François Roux, Bin Sun, Gregory J. Dore, Clemens A. Schmitt, Ricardo Iván Martínez-Zamudio, Lucas Robinson
Přispěvatelé: Institut Pasteur [Paris] (IP), MRC London Institute of Medical Sciences (LMC), Imperial College London, R.I.M.-Z. was supported by La Ligue Nationale Contre le Cancer and is a Mexican National Scientific and Technology Council (CONACYT) and Mexican National Researchers System (SNI) fellow. L.R. was supported by the Pasteur–Paris University (PPU) International Ph.D. Program and by the Fondation pour la Recherche Médicale (FRM). J.A.N.L.F.d.F. was supported by La Ligue Nationale Contre le Cancer. J.G. was supported by the Medical Research Council (MRC, MC_U120085810) and by a grant from Worldwide Cancer Research (WCR, 18-0215). O.B. was supported by the Pasteur–Weizmann Foundation, ANR–BMFT, the Fondation ARC pour la recherche sur le Cancer, La Ligue Nationale Contre le Cancer and INSERM–AGEMED. Research reported in this publication was supported by the National Cancer Institute of the National Institutes of Health under award number R01CA136533., Institut Pasteur [Paris]
Rok vydání: 2020
Předmět:
[SDV]Life Sciences [q-bio]
Epigenesis
Genetic
Histones
0302 clinical medicine
CHROMATIN IMMUNOPRECIPITATION
MESH: Animals
MESH: Epigenesis
Genetic
11 Medical and Health Sciences
Epigenesis
MESH: Histones
Regulation of gene expression
0303 health sciences
CELLULAR SENESCENCE
MESH: Gene Expression Regulation
MESH: Transcription Factor AP-1
Chromatin
Cell biology
030220 oncology & carcinogenesis
Female
Life Sciences & Biomedicine
EXPRESSION
Senescence
PROTEINS
Biology
Article
MESH: Chromatin
03 medical and health sciences
MESH: Mice
Inbred C57BL
Animals
Humans
Epigenetics
Enhancer
Transcription factor
JUN
030304 developmental biology
MESH: Humans
Science & Technology
LANDSCAPE
MESH: Transcriptome
MESH: Cellular Senescence
Cell Biology
Epigenome
Fibroblasts
06 Biological Sciences
Mice
Inbred C57BL
Transcription Factor AP-1
ENHANCERS
Gene Expression Regulation
MESH: Fibroblasts
Transcriptome
MESH: Female
Developmental Biology
Zdroj: Nat Cell Biol
Nature Cell Biology
Nature Cell Biology, 2020, 22 (7), pp.842-855. ⟨10.1038/s41556-020-0529-5⟩
Nature Cell Biology, Nature Publishing Group, 2020, 22 (7), pp.842-855. ⟨10.1038/s41556-020-0529-5⟩
ISSN: 1476-4679
1465-7392
DOI: 10.1038/s41556-020-0529-5
Popis: International audience; 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.
Databáze: OpenAIRE
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