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AP-1 imprints a reversible transcriptional programme of senescent cells

Item Type:Article
Title:AP-1 imprints a reversible transcriptional programme of senescent cells
Creators Name:Martínez-Zamudio, R.I. and Roux, P.F. and de Freitas, J.A.N.L.F. and Robinson, L. and Doré, G. and Sun, B. and Belenki, D. and Milanovic, M. and Herbig, U. and Schmitt, C.A. and Gil, J. and Bischof, O.
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.
Keywords:Cellular Senescence, Chromatin, Fibroblasts, Gene Expression Regulation, Genetic Epigenesis, Histones, Inbred C57BL Mice, Transcription Factor AP-1, Transcriptome, Animals, Mice
Source:Nature Cell Biology
Publisher:Nature Publishing Group
Page Range:842-855
Date:July 2020
Additional Information:Erratum in: Nat Cell Biol 22(10):1286-1288. Copyright © 2020, The Author(s), under exclusive licence to Springer Nature Limited
Official Publication:https://doi.org/10.1038/s41556-020-0529-5
External Fulltext:View full text on PubMed Central
PubMed:View item in PubMed

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