AP-1 Imprints a Reversible Transcriptional Programme of Senescent Cells
Creators
- 1. Rutgers Biomedical & Health Sciences, Rutgers University
- 2. Johnson & Johnson, Upstream Skin Research, 92130 Issy-les-Moulineaux, France
- 3. Institut Pasteur, INSERM U.993
- 4. Institut Pasteur, INSERM U993
- 5. MRC London Institute of Medical Sciences (LMS), Du Cane Road, London, W12 0NN, UK
- 6. Kepler University Hospital, Department of Hematology and Oncology, Johannes Kepler University, Krankenhausstraße 9, 4020 Linz, Austria
- 7. Charité - University Medical Center, Department of Hematology, Oncology and Tumor Immunology, Virchow Campus, and Molekulares Krebsforschungszentrum, Augustenburger Platz 1, 13353 Berlin, Germany
Description
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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Additional details
Related works
- Is cited by
- Journal article: 10.1038/s41556-020-0529-5 (DOI)