| Přispěvatelé: |
Organisation Nucléaire et Oncogenèse / Nuclear Organization and Oncogenesis, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Rutgers University [Newark], Rutgers University System (Rutgers), Université Sorbonne Paris Cité (USPC), Imperial College London, MRC London Institute of Medical Sciences (LMC), Equipe labellisée Ligue contre le Cancer, R.I.M-Z. was supported by La Ligue Nationale Contre le Cancer and was a Mexican National Scientific and Technology Council (CONACYT) and Mexican National Researchers System (SNI) fellow. Lucas Robinson was supported by the Pasteur - Paris University (PPU) International PhD Program and by the Fondation pour la Recherche Médicale (FRM). J.A.N.L.F.F. was supported by La Ligue Nationale Contre le Cancer. O.B was supported by the Pasteur Weizmann Foundation, ANR-BMFT, Fondation ARC pour la recherche sur le Cancer, La Ligue Nationale Contre le Cancer, INSERM-AGEMED. Research reported in this publication was supported by the National Cancer Institute of the National Institutes of Health under Award Number R01CA136533, We thank all members, in particular Nir Rozenblum, of the O.B. laboratory for fruitful discussions and suggestions through the course of this work. We would like to thank the Transcriptome and Epigenome facility of Institut Pasteur. We thank Claudia Chica for expert advice on ChIP-seq data processing. We thank Ido Amit and Deborah Winter for valuable discussion and technical support. We thank Benno Schwikowski for key insights and technical advice. We also thank Lars Zender, Eric Gilson, and Hinrich Gronemeyer for valuable intellectual input., Physiologie, Environnement et Génétique pour l'Animal et les Systèmes d'Elevage [Rennes] (PEGASE), AGROCAMPUS OUEST-Institut National de la Recherche Agronomique (INRA), Organisation Nucléaire et Oncogenèse, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM) |
| Popis: |
SUMMARYSenescent cells play important physiological- and pathophysiological roles in tumor suppression, tissue regeneration, and aging. While select genetic and epigenetic elements crucial for senescence induction were identified, the dynamics, underlying epigenetic mechanisms, and regulatory networks defining senescence competence, induction and maintenance remain poorly understood, precluding a deliberate therapeutic manipulation of these dynamic processes. Here, we show, using dynamic analyses of transcriptome and epigenome profiles, that the epigenetic state of enhancers predetermines their sequential activation during senescence. We demonstrate that activator protein 1 (AP-1) ‘imprints’ the senescence enhancer landscape effectively regulating transcriptional activities pertinent to the timely execution of the senescence program. We define and validate a hierarchical transcription factor (TF) network model and demonstrate its effectiveness for the design of senescence reprogramming experiments. Together, our findings define the dynamic nature and organizational principles of gene-regulatory elements driving the senescence program and reveal promising inroads for therapeutic manipulation of senescent cells. |
