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AP-1 imprints a reversible transcriptional programme of senescent cells.
Open accessAbstract
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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“This temporal regulation of senescence- associated phenotypes seems to be, at least in part, controlled by the sequential and dynamic activation of diverse transcriptional programmes and hierarchies 72-74 .”
From Senescence and cancer — role and therapeutic opportunities (2022) · cites this paper as [74]
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“Indeed, senescence- associated phenotypes are temporal and early- stage senescent cells are phenotypically different from late- stage senescent cells 72-74 .”
From Senescence and cancer — role and therapeutic opportunities (2022) · cites this paper as [74]
In the citing paper
“They demonstrated that a hierarchical transcription factor network defines the senescence transcriptional program and identified activator protein 1 (AP-1) as a master regulator that drives the transcriptional program of senescent cells thereby revealing promising pathways with therapeutic implications for modulation of senescence in vivo.”
From Mechanisms of Cellular Senescence: Cell Cycle Arrest and Senescence Associated Secretory Phenotype (2021) · cites this paper as Martínez-Zamudio et al., 2020
In the citing paper
“They demonstrated that a hierarchical transcription factor network defines the senescence transcriptional program and identified activator protein 1 (AP-1) as a master regulator that drives the transcriptional program of senescent cells thereby revealing promising pathways with therapeutic implications for modulation of senescence in vivo.”
From Mechanisms of Cellular Senescence: Cell Cycle Arrest and Senescence Associated Secretory Phenotype (2021) · cites this paper as Martínez-Zamudio et al., 2020
In the citing paper
“A recent study by Martínez-Zamudio et al. (2020), revealed links between enhancer chromatin, transcription factor recruitment, and senescence competence.”
From Mechanisms of Cellular Senescence: Cell Cycle Arrest and Senescence Associated Secretory Phenotype (2021) · cites this paper as Martínez-Zamudio et al., 2020
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The jun proto-oncogene is positively autoregulated by its product, Jun/AP-1
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Senescence-associated reprogramming promotes cancer stemness
Milanovic, M., Fan, D. N. Y., Belenki, D., Däbritz, J. H. M., Zhao, Z., Yu, Y., Dörr, J. R., Dimitrova, L., Lenze, D., Monteiro Barbosa, I. A., et al. (2018) · Nature · doi:10.1038/nature25167 · Cited by 1,131
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Xu, P., Wang, M., Song, W.-M., Wang, Q., Yuan, G., Sudmant, P. H., Zare, H., Tu, Z., Orr, M. E., & Zhang, B. (2022) · Figshare · doi:10.6084/m9.figshare.18094446
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“DISCUSSION Our results revealed that AP-1, a pioneer factor for senescence 45 and aging-related chromatin opening 46 , plays a positive role in adaptive responses to exercise, a lifestyle intervention that counteracts aging and extends lifespan.”
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“This widespread opening incidentally exposes motifs for other factors—both lineage-defining and stress-responsive proteins, such as the AP-1 complex—which, with age and chronic stress, increasingly occupy stress-response chromatin and act as pioneer factors, keeping those regions open [53–56].”
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Metadata
- Authors
- Martínez-Zamudio, R. I., Roux, P.-F., de Freitas, J. A. N. L. F., Robinson, L., Doré, G., Sun, B., Belenki, D., Milanovic, M., Herbig, U., Schmitt, C. A., Gil, J., & Bischof, O.
- Affiliations
- Inserm (FR)
- MRC London Institute of Medical Sciences (GB)
- Max Delbrück Center (DE)
- Deutsches Konsortium für Translationale Krebsforschung (DE)
- Rutgers, The State University of New Jersey (US)
- Johannes Kepler University of Linz (AT)
- Corresponding author
- Bischof, Oliver
- ORCID
- Venue
- Nature Cell Biology
- Published
- 2020-06-08
- Volume
- 22
- Issue
- 7
- Pages
- 842-855
- ISSN
- 1465-7392 (ISSN-L)
- 1476-4679
- PMC
- PMC7899185
- OpenAlex
- W3033840227
- Cited by
- 236
- References
- 48
- Citations by year
- 2026: 38 · 2025: 40 · 2024: 39 · 2023: 51 · 2022: 35 · 2021: 26 · 2020: 7
- FWCI
- 18.64
- Type
- journal article
- Language
- en
- Update notices
- correction (2020-09-16)
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature Cell Biology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- HAL (submittedVersion)
- MDC Repository (Max-Delbrueck-Center for Molecular Medicine) (submittedVersion)
- Spiral (Imperial College London) (submittedVersion)
- Funders
- Cancer Research UK (28647)
- Agence Nationale de la Recherche (ANR-19-CE13-0017)
- National Cancer Institute (R01CA136533)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Keywords
- cellular senescence, AP-1, transcriptional regulatory networks, epigenetic regulation, Ras-induced senescence, transcriptional programs, transcription factor recruitment, time-resolved transcriptomics, senescence therapy
- MeSH terms
- Animals, Chromatin, Female, Fibroblasts, Gene Expression Regulation, Histones, Humans, Mice, Inbred C57BL, Cellular Senescence, Transcription Factor AP-1, Epigenesis, Genetic, Transcriptome
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