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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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In the citing paper
“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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“During ageing, this coordination breaks down, allowing activator protein 1 (AP-1)-mediated enhancer hijacking and promoting the expression of senescence-associated secretory phenotype (SASP) and other inflammation genes, which disrupts cellular functions 43,134 .”
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“Indeed, in the context of RIS, AP-1 has been shown to act as an early pioneer factor to pre-mark the landscape of enhancers [86].”
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“The AP1 family can not only drive cellular senescence such as oncogenic and replicative senescence 37,38 but also plays a role in in fl ammageing, where an upregulation of the AP1 family members JunandFoshasbeenobserved 102 .”
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“Indeed, AP-1 is essential for the expression of SASP genes in different cellular contexts (OIS and therapy-induced senescence or TIS) indicating that it is a master regulator of cellular senescence [169].”
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“…studies on OIS and replicative senescence performed in distinct cells have revealed a role for the AP-1 family in reshaping open chromatin upon senescence entry, which is in accordance with the enrichment of the bZIP family (a total set of AP-1) at SAAs discovered in our study [37, 38] (Fig.”
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Could senescence phenotypes strike the balance to promote tumor dormancy?
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“This alters the landscape of activated enhancers and organizes the regulation of the transcriptional program of genes related to senescence [78].”
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Wang, L., Donahue, G., Zhang, C., Havas, A. P., Lei, X., Xu, C., Wang, W., Vahedi, G., Adams, P. D., & Berger, S. L. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.05.22.541769 · Cited by 8
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“Furthermore, the activator protein AP-1 can reverse oncogene RAS-induced senescence (26).”
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Transcription factor network dynamics during the commitment to oncogene-induced senescence
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Self-citationThe single-cell immune landscape of HIV-associated aggressive B-cell lymphoma
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“Several studies have pinpointed transcriptional activation of AP-1 as a prominent and conserved signature of both activation and senescence of T cell, altering chromatin opening and remodeling enhancer landscape.”
Single-Cell Sequencing Reveals the Novel Role of Ezh2 in NK Cell Maturation and Function
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“The AP-1 family is a pioneer transcription factor (TF) family with an important role in establishing new cell fate competence by granting long-term chromatin access to nonpioneer factors and is also a crucial determinant of cell identity through opening and licensing of the enhancer landscape (41, 42).”
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“Glycolysis and SASP (co-expression of HK2 upregulation and IL-6 upregulation) 77,78 ; AP-1/TEAD1 → activation of proinflammatory genes 81,82 ; NAD + depletion → decreased SIRTs → increased histone acetylation → NF-κ B activation.”
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Cellular Senescence Triggered by Food and Environmental Genotoxins
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“The main transcription factors involved in the regulation of this process are C/EBP β [67], NF-κ B [68] c-Myc [69] and AP1 [70].”
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“AP-1 has been proposed as a master regulator of multiple enhancers associated with cell-state transitions including pluripotency 44 and senescence, 45 raising the possibility that SMARCB1-induced enhancer reprogramming may simply reflect increased expression of c-JUN following SMARCB1 restoration.”
Ablation of histone H1.4 reveals the focal regulation of AP-1 directed enhancers
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“Two others ( Jun, Atf2 ) encode subunits of the AP-1 transcriptional factor, which together with Sp1 can play a key role in reprogramming 21 .”
BackgroundInflammatory Transformation of Skin Basal Cells as a Key Driver of Cutaneous Aging
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“4c). bZip TFs, particularly AP-1 superfamily members (e.g., JUN, ATF7, and FOSL2), were found to exhibit increased activity and a continuously increase in chromatin binding during OIS, corroborating previousreports 39,40 .”
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“Here, the FOS/JUN (AP-1) TF, which primes reversible cellular senescence [71], could activate the FOS-mediated stress-response downstream from ERK [72], which is concurrently a component of the “female pregnancy” module created by MS [65,73].”
Etoh, K., Hino, Y., Morishita, H., & Nakao, M. (2026) · Molecular Cell · doi:10.1016/j.molcel.2026.03.020 · Cited by 2
Spurious transcription may be a hallmark of aging
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Cherfils‐Vicini, J., & Gilson, É. (2020) · médecine/sciences · doi:10.1051/medsci/2020242 · Cited by 2
“Martínez-Zamudio RI, Roux P-F, Freitas JANLF de, et al. AP-1 imprints a reversible transcriptional programme of senescent cells.”
Lazar-Contes, I., Arzate‐Mejía, R. G., Tanwar, D. K., Steg, L. C., Uzel, K., Feudjio, O. U., Crespo, M., Germain, P., & Mansuy, I. M. (2020) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2020.08.20.259374 · Cited by 3
“JUN, FOS and CREB are all part of the AP-1 (activating protein-1) superfamily, and play an important role in regulating cell proliferation and death, by mediating the senescence-associated chromatin and transcriptional landscape (Martínez-Zamudio et al., 2020; Shaulian and Karin, 2002).”
BackgroundThe AP-1 factors FOSL1 and FOSL2 co-regulate human Th17 responsesPreprint
Shetty, A., Tripathi, S. K., Junttila, S., Buchacher, T., Biradar, R., Bhosale, S. D., Envall, T., Laiho, A., Moulder, R., Rasool, O., et al. (2021) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2021.04.26.441472 · Cited by 2
“Many studies including ours, indicate that such binding convergence occurs over enhancer landscapes (73, 85, 141), which could drive CD4+ T cell differentiation programs (142).”
BackgroundA transcriptional cell atlas identifies the decline in the AT2 niche in aged human lungsPreprint
Liu, X., Zhang, X., Yao, C., Liang, J., Noble, P. W., & Jiang, D. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.06.16.545378 · Cited by 2
Steyaert, S., Verhelle, A., & Criekinge, W. V. (2023) · medRxiv · doi:10.1101/2023.07.07.23292381 · Cited by 2
“For example, the activation of the AP1 family of transcription factors was found to be barely represented in the RA group but prominent in the normal group, aligning with previous findings of diminished AP1 activity during ageing and in age-related diseases 66,67 .”
ResultLi, Y., Li, C., Zhou, Q. X., Liu, X., Qiao, Y., Xie, T., Sun, H., Ong, M. T., & Wang, H. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.06.20.599817 · Cited by 2
Antiaging for Ph-like ALL: targeting senescence
Iacobucci, I. (2025) · Blood · doi:10.1182/blood.2024027815 · Cited by 2
Activator protein-1 in liver pathology: from precancerous diseases to hepatocellular carcinoma
Villarruel-Melquiades, F., Aguirre-Maldonado, I., Herrera-López, E. E., Mendoza‐Garrido, M. E., Pérez‐Carreón, J. I., Bañuelos, C., & Camacho, J. (2024) · Hepatoma Research · doi:10.20517/2394-5079.2024.95 · Cited by 2
Balancing senescence and apoptosis: therapeutic insights into aging and cancer
Jan, N., Sofi, S., Mir, A. A., Masoodi, G., & Mir, M. A. (2025) · Molecular and Cellular Biochemistry · doi:10.1007/s11010-025-05355-3 · Cited by 1
“The sequential and dynamic activation of several transcriptional programs and hierarchies appears to be partially responsible for the temporal regulation of senescence-associated traits [129].”
Alarcón-Apablaza, J., Salazar, L. A., Loren, P., Martínez, C., & Fuentes, R. (2025) · Biomedicines · doi:10.3390/biomedicines13112776 · Cited by 1
Rentschler, M., Ali-Jarboui, M., Griessinger, C. M., Rosen, M., Doré, G. R. G., Bischof, O., Kneilling, M., Röcken, M., Braumüller, H., & Wieder, T. (2026) · GeroScience · doi:10.1007/s11357-026-02100-6 · Cited by 1
“…end point, an integrative, time-resolved analysis of transcriptome and epigenome changes in senescence revealed a hierarchically organized, modular, and dynamic transcription factor network orchestrated by the activator protein 1 (AP-1) acting as a pioneer of the senescence enhancer landscape [22].”
Self-citationZhang, Z., Wang, Z., Zhu, L., Chen, T., Chen, R., Wu, Z., Chen, J., Zhang, H., Wang, M., Liu, J., et al. (2026) · Journal of Advanced Research · doi:10.1016/j.jare.2026.01.073 · Cited by 1
“This finding is consistent with previous studies that linked AP-1 to the enhancer landscape in senescent cells [41].”
Remembrance of inflammations past
Qiu, C., & Shendure, J. (2026) · Nature · doi:10.1038/d41586-026-00639-0 · Cited by 1
Cellular senescence in skeletal muscle regeneration
Liu, X., & Wang, H. (2026) · Cell Regeneration · doi:10.1186/s13619-026-00287-9 · Cited by 1
Tanycyte BMAL1 regulates high-fat diet weight gain and shapes arcuate neurogenesis in female mice
Iascone, D. M., Pivarshev, P., Yang, J., Valencia, M. L., Noya, S. B., Lin, H., Holman, C. D., Anafi, R. C., Bedont, J. L., & Sehgal, A. (2026) · Cell Reports · doi:10.1016/j.celrep.2026.117685 · Cited by 1
“28 Several transcripts are also associated with aspects of neuronal differentiation, including Necdin (differentiation and survival of postmitotic neurons), 26 Macf1 (neurite outgrowth and migration), 29 Jun (associated with post-mitotic neurons more than neural precursors in adult neurogenesis),…”
Xu, Z., Guo, J., Liu, Z., Yu, J., Yuan, R., Min, Y., Wei, Z., & Peng, X. (2026) · Ageing Research Reviews · doi:10.1016/j.arr.2026.103270 · Cited by 1
Novel Role of Mammalian Cell Senescence‐Sustenance of Muscle Larvae of Trichinella spp
Dąbrowska, M., Kępczyńska, A., Goździk, K., Całka-Kresa, M., Skoneczny, M., Zieliński, Z., Doligalska, M., & Sikora, E. (2022) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2022/1799839 · Cited by 1
“It was shown to determine the pattern of active enhancers and the interactions within the network of active transcription factors [24].”
Systematic transcriptomic analysis and temporal modelling of the senescent human fibroblastPreprint
Scanlan, R.-L., Pease, L., O’Keefe, H., Guimera, A. M., Shanley, D., & Wordsworth, J. (2022) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2022.08.16.504144 · Cited by 1
Liu, J., Copland, D. A., Clare, A. J., Gorski, M., Richards, B. T., Scott, L. M., Theodoropoulou, S., Greferath, U., Cox, K. H. M., Bell, O. H., et al. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.09.27.559733 · Cited by 1
“A recent genome-wide profiling study indicated that 593 AP-1 functioned as a governing agent in the senescence programme by shaping the enhancer 594 landscape and determining the dynamic hierarchy of the transcription factor network leading to 595 senescence (73).”
Fantuz, M., Liebig, J., Fontana, G., Iebba, V., Carbone, C., Lukassen, S., Conrad, C., & Carrer, A. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.07.04.600210 · Cited by 1
“This aligns with the notion that AP-1 family members could dictate enhancer selection and possibly function as pioneer factors 50–52 , rather than only mediate acute stress responses.”
BackgroundSchiffman, A., Zhang, C., Ourthiague, D., & Hoffmann, A. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.02.04.636520 · Cited by 1
“…only IRF and NF B as the key regulators of IFN expression, as early studies noted that AP1 and NF κ B activation is always coordinated (52–55) and interdependent (56), and more recent studies described AP1’s function as a marker for open chromatin rather than a transcriptional activator (57, 58).”
Spurious intragenic transcription is a hallmark of mammalian cellular senescence and tissue agingPreprint
Sen, P., Donahue, G., Li, C., Lan, Y., Egervári, G., Robertson, N., Shah, P. P., Kerkhoven, E., Schultz, D., Adams, P. D., et al. (2022) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2022.05.20.492816
Biphasic JNK–Erk Signaling Separates Induction and Maintenance of Cell Senescence after DNA DamagePreprint
Netterfield, T. S., Ostheimer, G. J., Tentner, A. R., Sorger, P. K., Janes, K. A., Lauffenburger, D. A., & Yaffe, M. B. (2022) · SSRN Electronic Journal · doi:10.1101/2022.06.15.496288
“Martinez-Zamudio et al. (Martínez-Zamudio et al., 2020) used a combination of transcriptomic, ATAC-Seq and ChIP-Seq data to nominate AP-1 as a pioneering transcription factor that altered chromatin structure and allowed the establishment of a senescence-inducing enhancer landscape following the…”
MethodThe 6th international cell senescence association conference
Kawamoto, S., Matsumoto, T., Takasugi, M., & Hara, E. (2022) · Genes to Cells · doi:10.1111/gtc.12970
Lu, J., Ji, M.-L., Li, Z., Chang, Q., Geng, R., Zhou, Z. W., & Lin, Y. C. (2022) · Research Square · doi:10.21203/rs.3.rs-1645805/v1
What is hidden behind a pulmonary hypertensive, fibrotic and inflammatory phenotype?
Adnot, S., Lipskaia, L., & Bischof, O. (2022) · European Respiratory Journal · doi:10.1183/13993003.01301-2022
Self-citationWollenzien, H., Tecleab, Y. A., Sloane, R. A. S., Restaino, A. C., & Kareta, M. S. (2022) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2022.10.20.513051
“Members of the AP-1 network including Jun and Fos are indeed implicated in tumor development (49-59) although their role has not yet been characterized in SCLC.”
BackgroundPietrogrande, G., Shaker, M. R., Stednitz, S. J., Soheilmoghaddam, M., Aguado, J., Morrison, S. D., Zambrano, S., Tabassum, T., Javed, I., Cooper-White, J. J., et al. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.08.29.555421
JUN mediates senescence and immune cell recruitment to prevent prostate cancer progressionPreprint
Redmer, T., Raigel, M., Sternberg, C., Ziegler, R., Probst, C., Lindner, D., Aufinger, A., Limberger, T., Trachtová, K., Kodajova, P., et al. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.11.29.569178
Sun, L., Liu, Z., Ning, K., Wu, Z., Chen, Z., Wu, Z., & Yin, X. (2023) · Figshare · doi:10.6084/m9.figshare.22600801
Xu, P., Wang, M., Song, W., Wang, Q., Yuan, G., Sudmant, P. H., Zare, H., Tu, Z., Orr, M. E., & Zhang, B. (2022) · Figshare · doi:10.6084/m9.figshare.18094452
Sun, L., Liu, Z., Ning, K., Wu, Z., Chen, Z., Wu, Z., & Yin, X. (2023) · Figshare · doi:10.6084/m9.figshare.22600795
Sun, L., Liu, Z., Ning, K., Wu, Z., Chen, Z., Wu, Z., & Yin, X. (2023) · Figshare · doi:10.6084/m9.figshare.22600792
Sun, L., Liu, Z., Ning, K., Wu, Z., Chen, Z., Wu, Z., & Yin, X. (2023) · Figshare · doi:10.6084/m9.figshare.22600798
Du, L., & Liu, C. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.04.15.589549
Fos/AP-1 as an Exemplar for the Study of Neuronal Activity-Dependent Gene Regulation
Griffith, E. C., & Greenberg, M. E. (2024) · Springer eBooks · doi:10.1007/978-3-031-68550-7_1 · Cited by 2
Tanycyte Bmal1 sex-specifically regulates weight gain and hypothalamic neurogenesis in female micePreprint
Iascone, D. M., Pivarshev, P., Yang, J., Valencia, M. L., Noya, S. B., Lin, H., Anafi, R. C., Bedont, J. L., & Sehgal, A. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.04.21.649851
“Members of the senescence-promoting AP-1 complex including Jun and FosB were also up-regulated (Martínez-Zamudio et al., 2020).”
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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