ATF3 drives senescence by reconstructing accessible chromatin profiles

Zhang, Chao; Zhang, Xuebin; Huang, Li; Guan, Yiting; Huang, Xiaoke; Tian, Xiao‐Li; Zhang, Lijun; Tao, Wei

doi:10.1111/acel.13315

Cited by 84Genomics and Chromatin DynamicsTelomeres, Telomerase, and SenescenceEpigenetics and DNA Methylation

ATF3 drives senescence by reconstructing accessible chromatin profiles

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Zhang, Chao, Zhang, Xuebin, Huang, Li, Guan, Yiting, Huang, Xiaoke, Tian, Xiao‐Li, Zhang, Lijun, Tao, Wei·2021·Aging Cell

DOI 10.1111/acel.13315PMC PMC7963335

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Abstract

Chromatin organization and transcriptional profiles undergo tremendous reordering during senescence. However, uncovering the regulatory mechanisms between chromatin reconstruction and gene expression in senescence has been elusive. Here, we depicted the landscapes of both chromatin accessibility and gene expression to reveal gene regulatory networks in human umbilical vein endothelial cell (HUVEC) senescence and found that chromatin accessibilities are redistributed during senescence. Particularly, the intergenic chromatin was massively shifted with the increased accessibility regions (IARs) or decreased accessibility regions (DARs), which were mainly enhancer elements. We defined AP‐1 transcription factor family as being responsible for driving chromatin accessibility reconstruction in IARs, where low DNA methylation improved binding affinity of AP‐1 and further increased the chromatin accessibility. Among AP‐1 transcription factors, we confirmed ATF3 was critical to reconstruct chromatin accessibility to promote cellular senescence. Our results described a dynamic landscape of chromatin accessibility whose remodeling contributes to the senescence program, we identified that AP‐1 was capable of reorganizing the chromatin accessibility profile to regulate senescence.

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Genes upregulated in at least three senescent populations included NFKB1, KLF6, and ATF3.
“These included the previously discussed TF NFKB1, known for SASP regulation, as well as KLF6 and ATF3, both implicated in p21 regulation and senescence establishment.61,62,63”
From Cellular senescence in human liver under normal aging and cancer (2026) · cites this paper as [63]
The Results section ('AP-1 promotes senescence by regulating chromatin accessibility in IARs'; page unavailable) reports that ATF3 promotes senescence and measures CDKN1A, the gene encoding p21, after ATF3 overexpression. It does not establish the cited sentence's corresponding claim about KLF6 or report that NFKB1, KLF6, and ATF3 were upregulated in at least three senescent populations. (LLM, conf=0.85)
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KLF6 and ATF3 are implicated in p21 regulation and senescence establishment.
“as well as KLF6 and ATF3, both implicated in p21 regulation and senescence establishment.61,62,63”
From Cellular senescence in human liver under normal aging and cancer (2026) · cites this paper as [63]
The Results section reports that ATF3 promotes senescence in HUVECs, and Figure 6(a) includes CDKN1A (p21) mRNA among the measurements after ATF3 overexpression. Our copy does not establish KLF6’s role in p21 regulation or senescence, so it supports only the ATF3 portion of the cited statement. (LLM, conf=0.85)
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<tt>edgeR</tt> : a Bioconductor package for differential expression analysis of digital gene expression data
Robinson, M. D., McCarthy, D. J., & Smyth, G. K. (2010) · Bioinformatics · doi:10.1093/bioinformatics/btp616 · Cited by 41,364 · see citing works
The Hallmarks of Aging
López-Otín, C., Blasco, M. A., Partridge, L., Serrano, M., & Kroemer, G. (2013) · Cell · doi:10.1016/j.cell.2013.05.039 · Cited by 14,982 · see citing works
The serial cultivation of human diploid cell strains
Hayflick, L., & Moorhead, P. S. (1961) · Experimental Cell Research · doi:10.1016/0014-4827(61)90192-6 · Cited by 8,508 · cited 1× · see citing works
“The mechanisms of senescence have historically been viewed as replicated senescence and stress induced senescence(de Magalhaes & Passos, 2018; Hayflick & Moorhead, 1961; Robert H. te Poele, 2002; Serrano, Lin, McCurrach, Beach, & Lowe, 1997).”
Background
A biomarker that identifies senescent human cells in culture and in aging skin in vivo.
Dimri, G. P., Lee, X., Basile, G., Acosta, M., Scott, G., Roskelley, C., Medrano, E. E., Linskens, M., Rubelj, I., & Pereira-Smith, O. (1995) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.92.20.9363 · Cited by 7,477 · cited 1× · see citing works
“The signals of SA-β-Gal and Ki-67 were gradually increased or decreased with the extension of HUVECs culture time, which are classical senescence or proliferation markers(Dimri et al., 1995; Gerdes et al., 1987)(Fig.”
Background
DNA methylation age of human tissues and cell types
Horvath, S. (2013) · Genome Biology · doi:10.1186/gb-2013-14-10-r115 · Cited by 7,075 · cited 1× · see citing works
“DNA methylation patterns can be used to estimate the state of cellular senescence which is referred as DNA methylation clock(Field et al., 2018; Franzen et al., 2017; Horvath, 2013).”
Background
Transposition of native chromatin for fast and sensitive epigenomic profiling of open chromatin, DNA-binding proteins and nucleosome position
Buenrostro, J. D., Giresi, P. G., Zaba, L. C., Chang, H. Y., & Greenleaf, W. J. (2013) · Nature Methods · doi:10.1038/nmeth.2688 · Cited by 6,422 · see citing works
Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a
Serrano, M., Lin, A. W., McCurrach, M. E., Beach, D., & Lowe, S. W. (1997) · Cell · doi:10.1016/s0092-8674(00)81902-9 · Cited by 5,178 · see citing works
Epigenetic differences arise during the lifetime of monozygotic twins
Fraga, M. F., Ballestar, E., Paz, M. F., Ropero, S., Setien, F., Ballestar, M. L., Heine-Suñer, D., Cigudosa, J. C., Urioste, M., Benitez, J., et al. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0500398102 · Cited by 3,602 · cited 1× · see citing works
“Epigenetics has been considered an extremely important contributor to senescence and aging(Fraga et al., 2005; Payel Sen, Shah, Nativio, & Berger, 2016).”
Background
AP-1 function and regulation
Karin, M., Liu, Z.-G., & Zandi, E. (1997) · Current Opinion in Cell Biology · doi:10.1016/s0955-0674(97)80068-3 · Cited by 2,904 · see citing works
The role of senescent cells in ageing
van Deursen, J. M. (2014) · Nature · doi:10.1038/nature13193 · Cited by 2,623 · cited 2× · see citing works
“20540 van Deursen, J. M. (2014). The role of senescent cells in ageing.”
Background
Single-cell chromatin accessibility reveals principles of regulatory variation
Buenrostro, J. D., Wu, B., Litzenburger, U. M., Ruff, D., Gonzales, M. L., Snyder, M. P., Chang, H. Y., & Greenleaf, W. J. (2015) · Nature · doi:10.1038/nature14590 · Cited by 2,308 · cited 1× · see citing works
“…we described the landscape of chromatin accessibility during HUVECs senescence using ATAC-seq which is a powerful tool to reveal the genome-wide chromatin accessibility based on hyperactive Tn5 transposase(J. D. Buenrostro, Giresi, Zaba, Chang, & Greenleaf, 2013; Jason D. Buenrostro et al., 2015).”
Method
Rb-mediated heterochromatin formation and silencing of E2F target genes during cellular senescence
Narita, M., Nuñez, S., Heard, E., Narita, M., Lin, A. W., Hearn, S. A., Spector, D. L., Hannon, G. J., & Lowe, S. W. (2003) · Cell · doi:10.1016/s0092-8674(03)00401-x · Cited by 2,278 · cited 1× · see citing works
“There exists a chromatin remodeling procedure in cell nucleus during senescence which involves the formation of senescence-associated heterochromatin foci (SAHF) in where specific proliferation-associated genes are repressed(Narita et al., 2006; Narita et al., 2003; R. Zhang et al., 2005).”
Background
Chromatin accessibility and the regulatory epigenome
Klemm, S. L., Shipony, Z., & Greenleaf, W. J. (2019) · Nature Reviews Genetics · doi:10.1038/s41576-018-0089-8 · Cited by 1,793 · see citing works
Senescence in Health and Disease
He, S., & Sharpless, N. E. (2017) · Cell · doi:10.1016/j.cell.2017.05.015 · Cited by 1,766 · cited 1× · see citing works
“Senescent cells play intricate roles in many biological processes including tumor suppression, embryogenesis, tissue repair, host immunity, aging and age-related disorders(Chou & Effros, 2013; He & Sharpless, 2017; Jun & Lau, 2010; Munoz-Espin et al., 2013; Reddel, 2009; Storer et al., 2013).”
Background
AP-1 in cell proliferation and survival
Shaulian, E., & Karin, M. (2001) · Oncogene · doi:10.1038/sj.onc.1204383 · Cited by 1,733 · cited 1× · see citing works
“AP-1 transcription factors including ATF, Fos and Jun participate in a wide range of cellular program like proliferation and apoptosis (Ameyar, Wisniewska, & Weitzman, 2003; Karin, Liu, & Zandi, 1997; Shaulian & Karin, 2001).”
Background
A growth-deficiency phenotype in heterozygous mice carrying an insulin-like growth factor II gene disrupted by targeting
DeChiara, T. M., Efstratiadis, A., & Robertsen, E. J. (1990) · Nature · doi:10.1038/345078a0 · Cited by 1,663 · see citing works
Programmed cell senescence during mammalian embryonic development
Muñoz-Espín, D., Cañamero, M., Maraver, A., Gómez-López, G., Contreras, J., Murillo-Cuesta, S., Rodríguez-Baeza, A., Varela-Nieto, I., Ruberte, J., Collado, M., et al. (2013) · Cell · doi:10.1016/j.cell.2013.10.019 · Cited by 1,428 · cited 1× · see citing works
“Senescent cells play intricate roles in many biological processes including tumor suppression, embryogenesis, tissue repair, host immunity, aging and age-related disorders(Chou & Effros, 2013; He & Sharpless, 2017; Jun & Lau, 2010; Munoz-Espin et al., 2013; Reddel, 2009; Storer et al., 2013).”
Background
A proteomic atlas of senescence-associated secretomes for aging biomarker development
Basisty, N., Kale, A., Jeon, O. H., Kuehnemann, C., Payne, T., Rao, C., Holtz, A., Shah, S., Sharma, V., Ferrucci, L., et al. (2020) · PLOS Biology · doi:10.1371/journal.pbio.3000599 · Cited by 1,348 · see citing works
The chromatin accessibility landscape of primary human cancers
Corces, M. R., Granja, J. M., Shams, S., Louie, B. H., Seoane, J. A., Zhou, W., Silva, T. C., Groeneveld, C., Wong, C. K., Cho, S. W., et al. (2018) · Science · doi:10.1126/science.aav1898 · Cited by 1,230 · cited 1× · see citing works
“The analyses of chromatin accessibility reveal the dynamic gene regulatory networks in various physiological and pathological processes(Cao et al., 2018; Corces et al., 2018; Gao et al., 2018; John et al., 2011; L. Liu et al., 2019; Y. Liu et al., 2018; Xie et al., 2020).”
Background
Senescence is a developmental mechanism that contributes to embryonic growth and patterning
Storer, M., Mas, A., Robert-Moreno, A., Pecoraro, M., Ortells, M. C., Di Giacomo, V., Yosef, R., Pilpel, N., Krizhanovsky, V., Sharpe, J., et al. (2013) · Cell · doi:10.1016/j.cell.2013.10.041 · Cited by 1,186 · cited 1× · see citing works
“Senescent cells play intricate roles in many biological processes including tumor suppression, embryogenesis, tissue repair, host immunity, aging and age-related disorders(Chou & Effros, 2013; He & Sharpless, 2017; Jun & Lau, 2010; Munoz-Espin et al., 2013; Reddel, 2009; Storer et al., 2013).”
Background
Lamin B1 loss is a senescence-associated biomarker
Freund, A., Laberge, R.-M., Demaria, M., & Campisi, J. (2012) · Molecular Biology of the Cell · doi:10.1091/mbc.e11-10-0884 · Cited by 1,046 · see citing works
The matricellular protein CCN1 induces fibroblast senescence and restricts fibrosis in cutaneous wound healing
Jun, J.-I., & Lau, L. F. (2010) · Nature Cell Biology · doi:10.1038/ncb2070 · Cited by 998 · cited 1× · see citing works
“Senescent cells play intricate roles in many biological processes including tumor suppression, embryogenesis, tissue repair, host immunity, aging and age-related disorders(Chou & Effros, 2013; He & Sharpless, 2017; Jun & Lau, 2010; Munoz-Espin et al., 2013; Reddel, 2009; Storer et al., 2013).”
Background
In Vivo Amelioration of Age-Associated Hallmarks by Partial Reprogramming.
Ocampo, A., Reddy, P., Martinez-Redondo, P., Platero-Luengo, A., Hatanaka, F., Hishida, T., Li, M., Lam, D., Kurita, M., Beyret, E., et al. (2016) · Cell · doi:10.1016/j.cell.2016.11.052 · Cited by 988 · cited 3× · see citing works
“A. Ocampo et.al ameliorated senescence and aging phenotype by short-term cyclic expression of Oct4, Sox2, Klf4, and c-Myc (OSKM)(Ocampo et al., 2016).”
Background
Unmasking Transcriptional Heterogeneity in Senescent Cells
Hernandez-Segura, A., de Jong, T. V., Melov, S., Guryev, V., Campisi, J., & Demaria, M. (2017) · Current Biology · doi:10.1016/j.cub.2017.07.033 · Cited by 972 · cited 2× · see citing works
“…PHGDH and other genes are downregulated in multiple senescence systems(Chan et al., 2019; Cho et al., 2019; Galanos et al., 2016; Hari et al., 2019; Hernandez-Segura et al., 2017; Komseli et al., 2018; Lau, Porciuncula, Yu, Iwakura, & David, 2019; Leveque et al., 2019; Q. Li et al., 2013; Limbad…”
BackgroundResult
Epigenetic mechanisms of longevity and aging
Sen, P., Shah, P. P., Nativio, R., & Berger, S. L. (2016) · Cell · doi:10.1016/j.cell.2016.07.050 · Cited by 956 · see citing works
Chromatin accessibility pre-determines glucocorticoid receptor binding patterns
John, S., Sabo, P. J., Thurman, R. E., Sung, M.-H., Biddie, S. C., Johnson, T. A., Hager, G. L., & Stamatoyannopoulos, J. A. (2011) · Nature Genetics · doi:10.1038/ng.759 · Cited by 954 · cited 1× · see citing works
“The analyses of chromatin accessibility reveal the dynamic gene regulatory networks in various physiological and pathological processes(Cao et al., 2018; Corces et al., 2018; Gao et al., 2018; John et al., 2011; L. Liu et al., 2019; Y. Liu et al., 2018; Xie et al., 2020).”
Background
Epigenetics and aging
Pal, S., & Tyler, J. K. (2016) · Science Advances · doi:10.1126/sciadv.1600584 · Cited by 860 · cited 1× · see citing works
“The epigenome serves as a bridge connecting the genotype with the phenotype which is responsible to interpret the information of genome(Pal & Tyler, 2016).”
Background
Formation of MacroH2A-Containing Senescence-Associated Heterochromatin Foci and Senescence Driven by ASF1a and HIRA
Zhang, R., Poustovoitov, M. V., Ye, X., Santos, H. A., Chen, W., Daganzo, S. M., Erzberger, J. P., Serebriiskii, I. G., Canutescu, A. A., Dunbrack, R. L., et al. (2005) · Developmental Cell · doi:10.1016/j.devcel.2004.10.019 · Cited by 699 · cited 1× · see citing works
“There exists a chromatin remodeling procedure in cell nucleus during senescence which involves the formation of senescence-associated heterochromatin foci (SAHF) in where specific proliferation-associated genes are repressed(Narita et al., 2006; Narita et al., 2003; R. Zhang et al., 2005).”
Background
DNA Methylation Decreases in Aging But Not in Immortal Cells
Wilson, V. L., & Jones, P. A. (1983) · Science · doi:10.1126/science.6844925 · Cited by 649 · cited 1× · see citing works
“Demethylation of whole genome was taken place while local hypermethylation still exist during replicative senescence(Hazel A. Cruickshanks et al., 2013; Wilson & Jones, 1983).”
Background
Untitled work
(2002) · PubMed · Cited by 640 · see citing works
A novel role for high-mobility group A proteins in cellular senescence and heterochromatin formation
Narita, M., Narita, M., Krizhanovsky, V., Nuñez, S., Chicas, A., Hearn, S. A., Myers, M. P., & Lowe, S. W. (2006) · Cell · doi:10.1016/j.cell.2006.05.052 · Cited by 629 · cited 1× · see citing works
“There exists a chromatin remodeling procedure in cell nucleus during senescence which involves the formation of senescence-associated heterochromatin foci (SAHF) in where specific proliferation-associated genes are repressed(Narita et al., 2006; Narita et al., 2003; R. Zhang et al., 2005).”
Background
DNA Methylation Clocks in Aging: Categories, Causes, and Consequences
Field, A. E., Robertson, N., Wang, T., Havas, A. P., Ideker, T., & Adams, P. D. (2018) · Molecular Cell · doi:10.1016/j.molcel.2018.08.008 · Cited by 622 · cited 6× · see citing works
“(2018). Functional CRISPR screen identifies AP1-associated enhancer”
BackgroundInfluential
A Werner syndrome stem cell model unveils heterochromatin alterations as a driver of human aging
Zhang, W., Li, J., Suzuki, K., Qu, J., Wang, P., Zhou, J., Liu, X., Ren, R., Xu, X., Ocampo, A., et al. (2015) · Science · doi:10.1126/science.aaa1356 · Cited by 551 · cited 1× · see citing works
“For examples, H3K9me3 is reduced in Werner syndrome model cells (W. Zhang et al., 2015), decrease of H4K16ac is observed in Zmpste-24-null fibroblasts(Krishnan et al., 2011), loss of H4K20me3 promotes senescence and aging (Lyu et al., 2018).”
Background
Lamin B1 depletion in senescent cells triggers large-scale changes in gene expression and the chromatin landscape
Shah, P. P., Donahue, G., Otte, G. L., Capell, B. C., Nelson, D. M., Cao, K., Aggarwala, V., Cruickshanks, H. A., Rai, T. S., McBryan, T., et al. (2013) · Genes & Development · doi:10.1101/gad.223834.113 · Cited by 550 · see citing works
Reorganization of enhancer patterns in transition from naive to primed pluripotency
Buecker, C., Srinivasan, R., Wu, Z., Calo, E., Acampora, D., Faial, T., Simeone, A., Tan, M., Swigut, T., & Wysocka, J. (2014) · Cell Stem Cell · doi:10.1016/j.stem.2014.04.003 · Cited by 507 · cited 1× · see citing works
“It is worth noting that there distributes strong enhancer in the IARs near FGF5 (Buecker et al., 2014).”
Background
Transcription Factor AP1 Potentiates Chromatin Accessibility and Glucocorticoid Receptor Binding
Biddie, S. C., John, S., Sabo, P. J., Thurman, R. E., Johnson, T. A., Schiltz, R. L., Miranda, T. B., Sung, M.-H., Trump, S., Lightman, S. L., et al. (2011) · Molecular Cell · doi:10.1016/j.molcel.2011.06.016 · Cited by 503 · cited 2× · see citing works
“More and more evidences indicated that AP-1 is responsible for establishment and maintenance of open chromatin orchestrating with gene expression in multiple cell types which partially function as a pioneer factor (Biddie et al., 2011; Britton et al., 2017; Kurachi et al., 2014; Vierbuchen et al., 2017).”
Background
A human-like senescence-associated secretory phenotype is conserved in mouse cells dependent on physiological oxygen.
Coppé, J.-P., Patil, C. K., Rodier, F., Krtolica, A., Beauséjour, C. M., Parrinello, S., Hodgson, J. G., Chin, K., Desprez, P.-Y., & Campisi, J. (2010) · PLoS ONE · doi:10.1371/journal.pone.0009188 · Cited by 455 · cited 2× · see citing works
“For examples, the significantly upregulated genes IGFBP6(Coppe et al., 2010), KLF2(Taniguchi et al., 2012), LAMB3(Denisenko, Mar, Trawczynski, & Bomsztyk, 2018), FOXA1(Q. Li et al., 2013), TGFB1(Senturk et al., 2010), their chromatin accessibility is also increased remarkably with senescence.”
Background
AP-1 Transcription Factors and the BAF Complex Mediate Signal-Dependent Enhancer Selection
Vierbuchen, T., Ling, E., Cowley, C. J., Couch, C. H., Wang, X., Harmin, D. A., Roberts, C. W. M., & Greenberg, M. E. (2017) · Molecular Cell · doi:10.1016/j.molcel.2017.11.026 · Cited by 455 · cited 3× · see citing works
“More and more evidences indicated that AP-1 is responsible for establishment and maintenance of open chromatin orchestrating with gene expression in multiple cell types which partially function as a pioneer factor (Biddie et al., 2011; Britton et al., 2017; Kurachi et al., 2014; Vierbuchen et al., 2017).”
Background
Effects of p21 <sup>Waf1/Cip1/Sdi1</sup> on cellular gene expression: Implications for carcinogenesis, senescence, and age-related diseases
Chang, B.-D., Watanabe, K., Broude, E. V., Fang, J., Poole, J. C., Kalinichenko, T. V., & Roninson, I. B. (2000) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.97.8.4291 · Cited by 432 · cited 2× · see citing works
“The expression of CDKN1A(Chang et al., 2000) and TGFBI(B.”
Background
BRD4 Connects Enhancer Remodeling to Senescence Immune Surveillance
Tasdemir, N., Banito, A., Roe, J.-S., Alonso-Curbelo, D., Camiolo, M., Tschaharganeh, D. F., Huang, C.-H., Aksoy, O., Bolden, J. E., Chen, C.-C., et al. (2016) · Cancer Discovery · doi:10.1158/2159-8290.cd-16-0217 · Cited by 415 · see citing works
The transcription factor BATF operates as an essential differentiation checkpoint in early effector CD8+ T cells
Kurachi, M., Barnitz, R. A., Yosef, N., Odorizzi, P. M., DiIorio, M. A., Lemieux, M. E., Yates, K. B., Godec, J., Klatt, M. G., Regev, A., et al. (2014) · Nature Immunology · doi:10.1038/ni.2834 · Cited by 384 · cited 2× · see citing works
“More and more evidences indicated that AP-1 is responsible for establishment and maintenance of open chromatin orchestrating with gene expression in multiple cell types which partially function as a pioneer factor (Biddie et al., 2011; Britton et al., 2017; Kurachi et al., 2014; Vierbuchen et al., 2017).”
Background
Senescent cells harbour features of the cancer epigenome
Cruickshanks, H. A., McBryan, T., Nelson, D. M., VanderKraats, N. D., Shah, P. P., van Tuyn, J., Singh Rai, T., Brock, C., Donahue, G., Dunican, D. S., et al. (2013) · Nature Cell Biology · doi:10.1038/ncb2879 · Cited by 358 · cited 2× · see citing works
“The DNA methylation of whole genome presents a broad decline and a local increase(H. A. Cruickshanks et al., 2013).”
Background
A role for AP-1 in apoptosis: the case for and against
Ameyar‐Zazoua, M., Wisniewska, M. B., & Weitzman, J. B. (2003) · Biochimie · doi:10.1016/j.biochi.2003.09.006 · Cited by 325 · see citing works
T Cell Replicative Senescence in Human Aging
P. Chou, J., & B. Effros, R. (2013) · Current Pharmaceutical Design · doi:10.2174/138161213805219711 · Cited by 323 · cited 1× · see citing works
“Senescent cells play intricate roles in many biological processes including tumor suppression, embryogenesis, tissue repair, host immunity, aging and age-related disorders(Chou & Effros, 2013; He & Sharpless, 2017; Jun & Lau, 2010; Munoz-Espin et al., 2013; Reddel, 2009; Storer et al., 2013).”
Background
Stress, cell senescence and organismal ageing
de Magalhães, J. P., & Passos, J. F. (2018) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2017.07.001 · Cited by 316 · see citing works
MYBL2 (B-Myb): a central regulator of cell proliferation, cell survival and differentiation involved in tumorigenesis
Musa, J., Aynaud, M.-M., Mirabeau, O., Delattre, O., & Grünewald, T. G. P. (2017) · Cell Death and Disease · doi:10.1038/cddis.2017.244 · Cited by 315 · see citing works
Independence of Repressive Histone Marks and Chromatin Compaction during Senescent Heterochromatic Layer Formation
Chandra, T., Kirschner, K., Thuret, J.-Y., Pope, B. D., Ryba, T., Newman, S., Ahmed, K., Samarajiwa, S. A., Salama, R., Carroll, T., et al. (2012) · Molecular Cell · doi:10.1016/j.molcel.2012.06.010 · Cited by 308 · see citing works
Transient non-integrative expression of nuclear reprogramming factors promotes multifaceted amelioration of aging in human cells.
Sarkar, T. J., Quarta, M., Mukherjee, S., Colville, A., Paine, P., Doan, L., Tran, C. M., Chu, C. R., Horvath, S., Qi, L. S., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-15174-3 · Cited by 308 · cited 2× · see citing works
“T. J. Sarkar et.al transiently expressed OCT4, SOX2, KLF4, c-MYC, LIN28, and NANOG (OSKMLN) in human cell partially reverted cellular senescence and restored aged tissue(Sarkar et al., 2020).”
Background
Chronic p53-independent p21 expression causes genomic instability by deregulating replication licensing
Galanos, P., Vougas, K., Walter, D., Polyzos, A., Maya-Mendoza, A., Haagensen, E. J., Kokkalis, A., Roumelioti, F.-M., Gagos, S., Tzetis, M., et al. (2016) · Nature Cell Biology · doi:10.1038/ncb3378 · Cited by 308 · see citing works
AKT induces senescence in human cells via mTORC1 and p53 in the absence of DNA damage: implications for targeting mTOR during malignancy
Astle, M. V., Hannan, K. M., Ng, P. Y., Lee, R. S., George, A. J., Hsu, A. K., Haupt, Y., Hannan, R. D., & Pearson, R. B. (2012) · Oncogene · doi:10.1038/onc.2011.394 · Cited by 295 · cited 1× · see citing works
“The up-regulated genes are mainly involved in the PI3K-Akt signaling pathway, which widely responds to external signals to regulate cell growth, but there are some reports that the activation of the PI3K-Akt signaling pathway possibly triggers senescence (Astle et al., 2012) which are consistent with our conclusion.”
Result
Ageing-related chromatin defects through loss of the NURD complex
Pegoraro, G., Kubben, N., Wickert, U., Goehler, H., Hoffmann, K., & Misteli, T. (2009) · Nature Cell Biology · doi:10.1038/ncb1971 · Cited by 293 · cited 1× · see citing works
“Loss of the components of NURD complex leads to ageing-related chromatin defects(Pegoraro et al., 2009).”
Background
DNA Methylation Increases Nucleosome Compaction and Rigidity
Choy, J. S., Wei, S., Lee, J. Y., Tan, S., Chu, S., & Lee, T.-H. (2010) · Journal of the American Chemical Society · doi:10.1021/ja910264z · Cited by 279 · cited 1× · see citing works
“Both the DNA methylation level and the condensed chromatin proportion were significantly decrease(Choy et al., 2010).”
Background
The heterochromatin loss model of aging
Villeponteau, B. (1997) · Experimental Gerontology · doi:10.1016/s0531-5565(96)00155-6 · Cited by 261 · cited 1× · see citing works
“While the local facultative heterochromatin is constructed, there is a global decrease of constitutive heterochromatin in senescence that is hypothesized as “heterochromatin loss model of aging”(Tsurumi & Li, 2012; Villeponteau, 1997).”
Background
Global heterochromatin loss
Tsurumi, A., & Li, W. X. (2012) · Epigenetics · doi:10.4161/epi.20540 · Cited by 248 · cited 1× · see citing works
“While the local facultative heterochromatin is constructed, there is a global decrease of constitutive heterochromatin in senescence that is hypothesized as “heterochromatin loss model of aging”(Tsurumi & Li, 2012; Villeponteau, 1997).”
Background
Lineage-specific DNA methylation in T cells correlates with histone methylation and enhancer activityPreprint
Schmidl, C., Klug, M., Boeld, T. J., Andreesen, R., Hoffmann, P., Edinger, M., & Rehli, M. (2009) · Genome Research · doi:10.1101/gr.091470.109 · Cited by 239 · see citing works
Transforming Growth Factor-Beta Induces Senescence in Hepatocellular Carcinoma Cells and Inhibits Tumor Growth†,‡
Şentürk, Ş., Mumcuoğlu, M., Gürsoy-Yüzügüllü, Ö., Cingoz, B., Akçalı, K. C., & Öztürk, M. (2010) · Hepatology · doi:10.1002/hep.23769 · Cited by 238 · cited 2× · see citing works
“For examples, the significantly upregulated genes IGFBP6(Coppe et al., 2010), KLF2(Taniguchi et al., 2012), LAMB3(Denisenko, Mar, Trawczynski, & Bomsztyk, 2018), FOXA1(Q. Li et al., 2013), TGFB1(Senturk et al., 2010), their chromatin accessibility is also increased remarkably with senescence.”
Background
Histone H4 lysine 16 hypoacetylation is associated with defective DNA repair and premature senescence in Zmpste24-deficient mice
Krishnan, V., Chow, M. Z. Y., Wang, Z., Zhang, L., Liu, B., Liu, X., & Zhou, Z. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1102789108 · Cited by 236 · cited 2× · see citing works
“, 2015), decrease of H4K16ac is observed in Zmpste-24-null fibroblasts(Krishnan et al., 2011), loss of H4K20me3 promotes senescence and aging (Lyu et al.”
BackgroundSelf-citation
AP-1 imprints a reversible transcriptional programme of senescent cells.
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., et al. (2020) · Nature Cell Biology · doi:10.1038/s41556-020-0529-5 · Cited by 236 · cited 2× · see citing works
“When our project was about to be completed, we found that Ricardo et al.(Martinez-Zamudio et al., 2020) recently published research on the regulation of AP-1 transcription factors to senescence program and our work can confirm and complement each other.”
Result
Tendon‐derived stem/progenitor cell aging: defective self‐renewal and altered fate
Zhou, Z., Akinbiyi, T., Xu, L., Ramcharan, M., Leong, D. J., Ros, S. J., Colvin, A. C., Schaffler, M. B., Majeska, R. J., Flatow, E. L., et al. (2010) · Aging Cell · doi:10.1111/j.1474-9726.2010.00598.x · Cited by 201 · cited 2× · see citing works
“…Porciuncula, Yu, Iwakura, & David, 2019; Leveque et al., 2019; Q. Li et al., 2013; Limbad et al., 2020; Lowe & Raj, 2014; Nagano et al., 2016; Pan et al., 2019; Pantazi et al., 2019; Suwan et al., 2009; Wu, Pepowski, Takahashi, & Kron, 2019; Zhou et al., 2010), as are consistent with our results.”
Result
Chromatin Accessibility Landscape in Human Early Embryos and Its Association with Evolution
Gao, L., Wu, K., Liu, Z., Yao, X., Yuan, S., Tao, W., Yi, L., Yu, G., Hou, Z., Fan, D., et al. (2018) · Cell · doi:10.1016/j.cell.2018.02.028 · Cited by 200 · cited 1× · see citing works
“The analyses of chromatin accessibility reveal the dynamic gene regulatory networks in various physiological and pathological processes(Cao et al., 2018; Corces et al., 2018; Gao et al., 2018; John et al., 2011; L. Liu et al., 2019; Y. Liu et al., 2018; Xie et al., 2020).”
BackgroundSelf-citation
Astrocyte senescence promotes glutamate toxicity in cortical neurons
Limbad, C., Oron, T. R., Alimirah, F., Davalos, A. R., Tracy, T. E., Gan, L., Desprez, P.-Y., & Campisi, J. (2020) · PLOS ONE · doi:10.1371/journal.pone.0227887 · Cited by 183 · cited 2× · see citing works
“…2019; Hernandez-Segura et al., 2017; Komseli et al., 2018; Lau, Porciuncula, Yu, Iwakura, & David, 2019; Leveque et al., 2019; Q. Li et al., 2013; Limbad et al., 2020; Lowe & Raj, 2014; Nagano et al., 2016; Pan et al., 2019; Pantazi et al., 2019; Suwan et al., 2009; Wu, Pepowski, Takahashi, &…”
Result
TGF-β signaling alters H4K20me3 status via miR-29 and contributes to cellular senescence and cardiac aging
Lyu, G., Guan, Y., Zhang, C., Zong, L., Sun, L., Huang, X., Huang, L., Zhang, L., Tian, X., Zhou, Z., et al. (2018) · Nature Communications · doi:10.1038/s41467-018-04994-z · Cited by 176 · cited 2× · see citing works
“, 2011), loss of H4K20me3 promotes senescence and aging (Lyu et al., 2018).”
BackgroundSelf-citation
Histone Acetyltransferase p300 Induces De Novo Super-Enhancers to Drive Cellular Senescence
Sen, P., Lan, Y., Li, C. Y., Sidoli, S., Donahue, G., Dou, Z., Frederick, B., Chen, Q., Luense, L. J., Garcia, B. A., et al. (2019) · Molecular Cell · doi:10.1016/j.molcel.2019.01.021 · Cited by 164 · cited 1× · see citing works
“Recently, a RNAi screening of epigenetic proteins indicated that p300 drives senescence mediated by de novo super enhancer formation(P. Sen et al., 2019).”
Background
HIRA orchestrates a dynamic chromatin landscape in senescence and is required for suppression of neoplasia
Rai, T. S., Cole, J. J., Nelson, D. M., Dikovskaya, D., Faller, W. J., Vizioli, M. G., Hewitt, R. N., Anannya, O., McBryan, T., Manoharan, I., et al. (2014) · Genes & Development · doi:10.1101/gad.247528.114 · Cited by 162 · see citing works
The innate immune sensor Toll-like receptor 2 controls the senescence-associated secretory phenotype
Hari, P., Millar, F. R., Tarrats, N., Birch, J., Quintanilla, A., Rink, C. J., Fernández-Duran, I., Muir, M., Finch, A. J., Brunton, V. G., et al. (2019) · Science Advances · doi:10.1126/sciadv.aaw0254 · Cited by 154 · see citing works
An integrated chromatin accessibility and transcriptome landscape of human pre-implantation embryos
Liu, L.-Q., Leng, L., Liu, C.-Y., Lu, C., Yuan, Y., Wu, L., Gong, F., Zhang, S.-P., Wei, X., Wang, M., et al. (2019) · Nature Communications · doi:10.1038/s41467-018-08244-0 · Cited by 124 · cited 1× · see citing works
“The analyses of chromatin accessibility reveal the dynamic gene regulatory networks in various physiological and pathological processes(Cao et al., 2018; Corces et al., 2018; Gao et al., 2018; John et al., 2011; L. Liu et al., 2019; Y. Liu et al., 2018; Xie et al., 2020).”
Background
PROGNOSTIC RELEVANCE OF TUMOUR-CELL GROWTH FRACTION IN MALIGNANT NON-HODGKIN'S LYMPHOMAS
Gerdes, J., Stein, H., Pileri, S. A., Rivano, M. T., Gobbi, M., Ralfkiaer, E. M., Nielsen, K., Pallesen, G., Bartels, H., Palestro, G., et al. (1987) · The Lancet · doi:10.1016/s0140-6736(87)90977-9 · Cited by 122 · cited 1× · see citing works
“The signals of SA-β-Gal and Ki-67 were gradually increased or decreased with the extension of HUVECs culture time, which are classical senescence or proliferation markers(Dimri et al., 1995; Gerdes et al., 1987)(Fig.”
Background
Uncoupling the Senescence-Associated Secretory Phenotype from Cell Cycle Exit via Interleukin-1 Inactivation Unveils Its Protumorigenic Role
Lau, L., Porciuncula, A., Yu, A., Iwakura, Y., & David, G. (2019) · Molecular and Cellular Biology · doi:10.1128/mcb.00586-18 · Cited by 119 · see citing works
Chromatin Accessibility Dynamics during Chemical Induction of Pluripotency
Cao, S., Yu, S., Li, D., Ye, J., Yang, X., Li, C., Wang, X., Mai, Y., Qin, Y., Wu, J., et al. (2018) · Cell Stem Cell · doi:10.1016/j.stem.2018.03.005 · Cited by 110 · cited 1× · see citing works
“The analyses of chromatin accessibility reveal the dynamic gene regulatory networks in various physiological and pathological processes(Cao et al., 2018; Corces et al., 2018; Gao et al., 2018; John et al., 2011; L. Liu et al., 2019; Y. Liu et al., 2018; Xie et al., 2020).”
Background
Silencing of Kruppel-like factor 2 by the histone methyltransferase EZH2 in human cancer
Taniguchi, H., Jacinto, F. V., Villanueva, A., Fernández, A. F., Yamamoto, H., Carmona, F. J., Puertas, S., Márquez, V. E., Shinomura, Y., Imai, K., et al. (2011) · Oncogene · doi:10.1038/onc.2011.387 · Cited by 108 · cited 2× · see citing works
“For examples, the significantly upregulated genes IGFBP6(Coppe et al., 2010), KLF2(Taniguchi et al., 2012), LAMB3(Denisenko, Mar, Trawczynski, & Bomsztyk, 2018), FOXA1(Q. Li et al., 2013), TGFB1(Senturk et al., 2010), their chromatin accessibility is also increased remarkably with senescence.”
Genomic methods in profiling DNA accessibility and factor localization
Klein, D. C., & Hainer, S. J. (2019) · Chromosome Research · doi:10.1007/s10577-019-09619-9 · Cited by 100 · cited 1× · see citing works
“4B)(Klein & Hainer, 2019; Sun, Miao, & Sun, 2019).”
Detect accessible chromatin using ATAC-sequencing, from principle to applications
Sun, Y., Miao, N., & Sun, T. (2019) · Hereditas · doi:10.1186/s41065-019-0105-9 · Cited by 93 · see citing works
Premature aging induced by radiation exhibits pro‐atherosclerotic effects mediated by epigenetic activation of CD 44 expression
Lowe, D., & Raj, K. (2014) · Aging Cell · doi:10.1111/acel.12253 · Cited by 92 · cited 1× · see citing works
“…et al., 2017; Komseli et al., 2018; Lau, Porciuncula, Yu, Iwakura, & David, 2019; Leveque et al., 2019; Q. Li et al., 2013; Limbad et al., 2020; Lowe & Raj, 2014; Nagano et al., 2016; Pan et al., 2019; Pantazi et al., 2019; Suwan et al., 2009; Wu, Pepowski, Takahashi, & Kron, 2019; Zhou et…”
Conserved senescence associated genes and pathways in primary human fibroblasts detected by RNA-seq
Marthandan, S., Baumgart, M., Priebe, S., Groth, M., Schaer, J., Kaether, C., Guthke, R., Cellerino, A., Platzer, M., Diekmann, S., et al. (2016) · PLOS ONE · doi:10.1371/journal.pone.0154531 · Cited by 91 · see citing works
Identification of cellular senescence-specific genes by comparative transcriptomics
Nagano, T., Nakano, M., Nakashima, A., Onishi, K., Yamao, S., Enari, M., Kikkawa, U., & Kamada, S. (2016) · Scientific Reports · doi:10.1038/srep31758 · Cited by 91 · cited 1× · see citing works
“Among them, FOXA1, PLAT, CD44, FGF5, DIO2 and other genes are upregulated, whereas PLCB1, SETBP1, EHD3, ZNF423, PHGDH and other genes are downregulated in multiple senescence systems(Chan et al., 2019; Cho et al., 2019; Galanos et al., 2016; Hari et al., 2019; Hernandez-Segura et al., 2017; Komseli et al., 2018; Lau,…”
Result
FOXM1 regulates proliferation, senescence and oxidative stress in keratinocytes and cancer cells
Smirnov, A., Panatta, E., Lena, A. M., Castiglia, D., Daniele, N. D., Melino, G., & Candi, E. (2016) · Aging · doi:10.18632/aging.100988 · Cited by 86 · see citing works
Senescence-activated enhancer landscape orchestrates the senescence-associated secretory phenotype in murine fibroblasts
Guan, Y., Zhang, C., Lyu, G., Zhang, X., Zhuang, T., Zhuang, T., Jia, L., Zhang, C., Zhang, C., Li, C., et al. (2020) · Nucleic Acids Research · doi:10.1093/nar/gkaa858 · Cited by 77 · see citing works
Self-citation
Senescence‐associated DNA methylation is stochastically acquired in subpopulations of mesenchymal stem cells
Franzen, J., Zirkel, A., Blake, J., Rath, B., Beneš, V., Papantonis, A., & Wagner, W. (2016) · Aging Cell · doi:10.1111/acel.12544 · Cited by 75 · cited 2× · see citing works
“DNA methylation patterns can be used to estimate the state of cellular senescence which is referred as DNA methylation clock(Field et al., 2018; Franzen et al., 2017; Horvath, 2013).”
BackgroundMethod
Replicative senescence: Considerations relating to the stability of heterochromatin domains
Howard, B. H. (1996) · Experimental Gerontology · doi:10.1016/0531-5565(95)00022-4 · Cited by 74 · cited 2× · see citing works
“It has been concerned several decades ago that chromatin structure changes have close connection with senescence(Howard, 1996; MacieiraCoelho, 1980, 1991).”
Background
Chromatin accessibility analysis reveals regulatory dynamics of developing human retina and hiPSC-derived retinal organoids
Xie, H., Zhang, W., Zhang, M., Akhtar, T., Li, Y., Yi, W., Sun, X., Zuo, Z.-Q., Wei, M., Fang, X., et al. (2020) · Science Advances · doi:10.1126/sciadv.aay5247 · Cited by 71 · see citing works
The role of TGFBI in mesothelioma and breast cancer: association with tumor suppression
Li, B., Wen, G., Zhao, Y., Tong, J., & Hei, T. K. (2012) · BMC Cancer · doi:10.1186/1471-2407-12-239 · Cited by 63 · see citing works
Chromatin accessibility landscape of articular knee cartilage reveals aberrant enhancer regulation in osteoarthritis
Liu, Y., Chang, J.-C., Hon, C.-C., Fukui, N., Tanaka, N., Zhang, Z., Lee, M. T. M., & Minoda, A. (2018) · Scientific Reports · doi:10.1038/s41598-018-33779-z · Cited by 63 · cited 1× · see citing works
“The analyses of chromatin accessibility reveal the dynamic gene regulatory networks in various physiological and pathological processes(Cao et al., 2018; Corces et al., 2018; Gao et al., 2018; John et al., 2011; L. Liu et al., 2019; Y. Liu et al., 2018; Xie et al., 2020).”
Background
Identification of CD44 as a senescence-induced cell adhesion gene responsible for the enhanced monocyte recruitment to senescent endothelial cells
Mun, G. I., & Boo, Y. C. (2010) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00835.2009 · Cited by 60 · see citing works
Brg1 chromatin remodeling factor is involved in cell growth arrest, apoptosis and senescence of rat mesenchymal stem cells
Napolitano, M. A., Cipollaro, M., Cascino, A., Melone, M. A. B., Giordano, A., & Galderisi, U. (2007) · Journal of Cell Science · doi:10.1242/jcs.004002 · Cited by 59 · cited 1× · see citing works
“Both silence and overexpression of brahma-related gene 1 (Brg1) which is the ATPase subunit of SWI/SNF complex could induce the cellular senescence in human or rat mesenchymal stem cells (MSCs) (Alessio et al., 2010; Napolitano et al., 2007).”
Background
Functional CRISPR screen identifies AP1-associated enhancer regulating FOXF1 to modulate oncogene-induced senescence
Han, R., Li, L., Ugalde, A. P., Tal, A., Manber, Z., Barberà, E. P., Chiara, V. D., Elkon, R., & Agami, R. (2018) · Genome biology · doi:10.1186/s13059-018-1494-1 · Cited by 53 · cited 1× · see citing works
“There were recent studies implied that AP-1 could drive breast cancer and oncogene induced senescence by regulating accessibility of specific promoter and enhancer(Han et al., 2018; Vierbuchen et al., 2017).”
Background
Versican/PG-M Assembles Hyaluronan into Extracellular Matrix and Inhibits CD44-mediated Signaling toward Premature Senescence in Embryonic Fibroblasts
Suwan, K., Choocheep, K., Hatano, S., et al. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m806927200 · Cited by 52 · cited 2× · see citing works
“…Porciuncula, Yu, Iwakura, & David, 2019; Leveque et al., 2019; Q. Li et al., 2013; Limbad et al., 2020; Lowe & Raj, 2014; Nagano et al., 2016; Pan et al., 2019; Pantazi et al., 2019; Suwan et al., 2009; Wu, Pepowski, Takahashi, & Kron, 2019; Zhou et al., 2010), as are consistent with our results.”
Result
Chromatin reorganization during senescence of proliferating cells
Macieira‐Coelho, A. (1991) · Mutation Research/DNAging · doi:10.1016/0921-8734(91)90003-t · Cited by 50 · cited 1× · see citing works
“It has been concerned several decades ago that chromatin structure changes have close connection with senescence(Howard, 1996; Macieira-Coelho, 1980, 1991).”
Background
Senescence: an antiviral defense that is tumor suppressive?
Reddel, R. R. (2009) · Carcinogenesis · doi:10.1093/carcin/bgp274 · Cited by 50 · cited 1× · see citing works
“Senescent cells play intricate roles in many biological processes including tumor suppression, embryogenesis, tissue repair, host immunity, aging and age-related disorders(Chou & Effros, 2013; He & Sharpless, 2017; Jun & Lau, 2010; Munoz-Espin et al., 2013; Reddel, 2009; Storer et al., 2013).”
Background
FOXA1 mediates p16INK4a activation during cellular senescence
Li, Q., Zhang, Y., Fu, J., Han, L., Xue, L., Lv, C., Wang, P., Li, G., & Tong, T. (2013) · The EMBO Journal · doi:10.1038/emboj.2013.35 · Cited by 49 · cited 2× · see citing works
“For examples, the significantly upregulated genes IGFBP6(Coppe et al., 2010), KLF2(Taniguchi et al., 2012), LAMB3(Denisenko, Mar, Trawczynski, & Bomsztyk, 2018), FOXA1(Q. Li et al., 2013), TGFB1(Senturk et al., 2010), their chromatin accessibility is also increased remarkably with senescence.”
Background
A prototypical non-malignant epithelial model to study genome dynamics and concurrently monitor micro-RNAs and proteins in situ during oncogene-induced senescence
Komseli, E.-S., Pateras, I. S., Krejsgaard, T., Stawiski, K., Rizou, S. V., Polyzos, A., Roumelioti, F., Chiourea, M., Mourkioti, I., Paparouna, E., et al. (2018) · BMC Genomics · doi:10.1186/s12864-017-4375-1 · Cited by 49 · cited 2× · see citing works
“Among them, FOXA1, PLAT, CD44, FGF5, DIO2 and other genes are upregulated, whereas PLCB1, SETBP1, EHD3, ZNF423, PHGDH and other genes are downregulated in multiple senescence systems(Chan et al., 2019; Cho et al., 2019; Galanos et al., 2016; Hari et al., 2019; Hernandez-Segura et al., 2017; Komseli et al., 2018; Lau,…”
Result
The BRG1 ATPase of chromatin remodeling complexes is involved in modulation of mesenchymal stem cell senescence through RB–P53 pathways
Alessio, N., Squillaro, T., Cipollaro, M., Bagella, L., Giordano, A., & Galderisi, U. (2010) · Oncogene · doi:10.1038/onc.2010.285 · Cited by 48 · cited 1× · see citing works
“Both silence and overexpression of brahma-related gene 1 (Brg1) which is the ATPase subunit of SWI/SNF complex could induce the cellular senescence in human or rat mesenchymal stem cells (MSCs) (Alessio et al., 2010; Napolitano et al., 2007).”
Background
Open chromatin profiling identifies AP1 as a transcriptional regulator in oesophageal adenocarcinoma
Britton, E., Rogerson, C., Mehta, S., Li, Y., Li, X., Fitzgerald, R. C., Ang, Y. S., & Sharrocks, A. D. (2017) · PLoS Genetics · doi:10.1371/journal.pgen.1006879 · Cited by 46 · cited 2× · see citing works
“More and more evidences indicated that AP-1 is responsible for establishment and maintenance of open chromatin orchestrating with gene expression in multiple cell types which partially function as a pioneer factor (Biddie et al., 2011; Britton et al., 2017; Kurachi et al., 2014; Vierbuchen et al., 2017).”
Background
An Endogenous Anti-aging Factor, Sonic Hedgehog, Suppresses Endometrial Stem Cell Aging through SERPINB2
Cho, A., Park, S.-R., Kim, S., Nam, S., Lim, S., Park, C. H., Lee, H., & Hong, I. (2019) · Molecular Therapy · doi:10.1016/j.ymthe.2019.04.019 · Cited by 45 · cited 2× · see citing works
“…are upregulated, whereas PLCB1, SETBP1, EHD3, ZNF423, PHGDH and other genes are downregulated in multiple senescence systems(Chan et al., 2019; Cho et al., 2019; Galanos et al., 2016; Hari et al., 2019; Hernandez-Segura et al., 2017; Komseli et al., 2018; Lau, Porciuncula, Yu, Iwakura, &…”
BackgroundResult
Implications of the Reorganization of the Cell Genome for Aging or Immortalization of Dividing Cells in vitro
Macieira‐Coelho, A. (2009) · Gerontology · doi:10.1159/000212428 · Cited by 42 · cited 1× · see citing works
“It has been concerned several decades ago that chromatin structure changes have close connection with senescence(Howard, 1996; Macieira-Coelho, 1980, 1991).”
Background
Cdkn1b overexpression in adult mice alters the balance between genome and tissue ageing
Pruitt, S. C., Freeland, A. L., Rusiniak, M. E., Kunnev, D., & Cady, G. K. (2013) · Nature Communications · doi:10.1038/ncomms3626 · Cited by 40 · see citing works
Identification of new genes associated to senescent and tumorigenic phenotypes in mesenchymal stem cells
Marques, J. C. M. T., Cornélio, D. A., Silbiger, V. N., Luchessi, A. D., de Souza, S., & de Medeiros, S. R. B. (2017) · Scientific Reports · doi:10.1038/s41598-017-16224-5 · Cited by 33 · cited 1× · see citing works
“Joana et al. also identified that DIO2 is highly expressed in the hMSCs senescence system, suggesting that DIO2 may be an alternative senescence marker(Medeiros Tavares Marques et al., 2017).”
Background
Integrins in senescence and aging
Borghesan, M., & O’Loghlen, A. (2017) · Cell Cycle · doi:10.1080/15384101.2017.1316573 · Cited by 31 · see citing works
Low-Dose Pesticide Mixture Induces Accelerated Mesenchymal Stem Cell Aging In Vitro
Lévêque, X. T., Hochane, M., Geraldo, F., Dumont, S., Gratas, C., Oliver, L., Gaignier, C., Trichet, V., Layrolle, P., Heymann, D., et al. (2019) · Stem Cells · doi:10.1002/stem.3014 · Cited by 29 · cited 2× · see citing works
“…2019; Galanos et al., 2016; Hari et al., 2019; Hernandez-Segura et al., 2017; Komseli et al., 2018; Lau, Porciuncula, Yu, Iwakura, & David, 2019; Leveque et al., 2019; Q. Li et al., 2013; Limbad et al., 2020; Lowe & Raj, 2014; Nagano et al., 2016; Pan et al., 2019; Pantazi et al., 2019; Suwan…”
Result
A Transcriptional Roadmap to the Senescence and Differentiation of Human Oral Keratinocytes
Jang, D. H., BHAWAL, U. K., Min, H.-K., Kang, H. K., Abiko, Y., & Min, B. (2014) · The Journals of Gerontology Series A · doi:10.1093/gerona/glt212 · Cited by 25 · see citing works
Inhibition of the 60S ribosome biogenesis GTPase LSG1 causes endoplasmic reticular disruption and cellular senescence
Pantazi, A., Quintanilla, A., Hari, P., Tarrats, N., Parasyraki, E., Dix, F. L., Patel, J., Chandra, T., Acosta, J. C., & Finch, A. J. (2019) · Aging Cell · doi:10.1111/acel.12981 · Cited by 22 · cited 2× · see citing works
“…Porciuncula, Yu, Iwakura, & David, 2019; Leveque et al., 2019; Q. Li et al., 2013; Limbad et al., 2020; Lowe & Raj, 2014; Nagano et al., 2016; Pan et al., 2019; Pantazi et al., 2019; Suwan et al., 2009; Wu, Pepowski, Takahashi, & Kron, 2019; Zhou et al., 2010), as are consistent with our results.”
Result
CIP2A- and SETBP1-mediated PP2A inhibition reveals AKT S473 phosphorylation to be a new biomarker in AML
Lucas, C., Scott, L. J., Carmell, N., Holcroft, A. K., Hills, R. K., Burnett, A. K., & Clark, R. E. (2018) · Blood Advances · doi:10.1182/bloodadvances.2017013615 · Cited by 20 · cited 2× · see citing works
“The significantly downregulated genes IGF2 (DeChiara, Efstratiadis, & Robertson, 1990), LMNB1, SETBP1(Lucas et al., 2018), CDKN1B(Pruitt, Freeland, Rusiniak, Kunnev, & Cady, 2013), SAMD12, their chromatin accessibility is also decreased remarkably with senescence (Fig.”
Background
Oxidative stress-induced cellular senescence desensitizes cell growth and migration of vascular smooth muscle cells through down-regulation of platelet-derived growth factor receptor-beta
Pan, C., Chen, C.-J., Shih, C., Wang, M.-F., Wang, J.-Y., & Wu, C. (2019) · Aging · doi:10.18632/aging.102270 · Cited by 19 · cited 2× · see citing works
“Among them, FOXA1, PLAT, CD44, FGF5, DIO2 and other genes are upregulated, whereas PLCB1, SETBP1, EHD3, ZNF423, PHGDH and other genes are downregulated in multiple senescence systems(Chan et al., 2019; Cho et al., 2019; Galanos et al., 2016; Hari et al., 2019; Hernandez-Segura et al., 2017; Komseli et al., 2018; Lau,…”
Result
Chromatin changes trigger laminin genes dysregulation in aging kidneys
Denisenko, O. N., Mar, D., Trawczynski, M., & Bomsztyk, K. (2018) · Aging · doi:10.18632/aging.101453 · Cited by 14 · see citing works
A cmap-enabled gene expression signature-matching approach identifies small-molecule inducers of accelerated cell senescence
Wu, D., Pepowski, B., Takahashi, S., & Kron, S. J. (2019) · BMC Genomics · doi:10.1186/s12864-019-5653-x · Cited by 13 · see citing works
Overexpression of iASPP is required for autophagy in response to oxidative stress in choriocarcinoma
Chan, K.-K., Wong, E. S. Y., Wong, I. T.-L., Cheung, C. L.-Y., Wong, O. G., Ngan, H., & Cheung, A. (2019) · BMC Cancer · doi:10.1186/s12885-019-6206-z · Cited by 10 · cited 2× · see citing works
“Among them, FOXA1, PLAT, CD44, FGF5, DIO2 and other genes are upregulated, whereas PLCB1, SETBP1, EHD3, ZNF423, PHGDH and other genes are downregulated in multiple senescence systems(Chan et al., 2019; Cho et al., 2019; Galanos et al., 2016; Hari et al., 2019; Hernandez-Segura et al., 2017; Komseli et al., 2018; Lau,…”
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Aging and aging-related diseases: from molecular mechanisms to interventions and treatments
Guo, J., Huang, X., Dou, L., Yan, M., Shen, T., Tang, W., & Li, J. (2022) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-022-01251-0 · Cited by 1,834 · see citing works
“During human umbilical vein endothelial cell (HUVEC) senescence, chromatin accessibility, mainly referring to intergenic chromatin along with increased accessibility regions (IARs) or decreased accessibility regions (DARs), is redistributed.(89) This process is mainly initiated by activating transcription factor 3 (AT…”
BackgroundInfluentialSelf-citation
Epigenetic regulation of aging: implications for interventions of aging and diseases
Kang, W., Liu, H., Hu, Q., Wang, L., Liu, J., Zheng, Z., Zhang, W., Ren, J., Zhu, F., & Liu, G. (2022) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-022-01211-8 · Cited by 694 · see citing works
“IARs mainly exist in genes related to the occurrence and development of aging, whereas DARs mainly exist in genes related to functional decline caused by aging.(136,137) The chromatin in human cells is spatially segregated into two compartments, compartment A and compartment B, and chromatin in the same compartment sh…”
Background
GDF15, an emerging key player in human aging
Conte, M., Giuliani, C., Chiariello, A., Iannuzzi, V., Franceschi, C., & Salvioli, S. (2022) · Ageing Research Reviews · doi:10.1016/j.arr.2022.101569 · Cited by 189 · see citing works
Exploring ER stress response in cellular aging and neuroinflammation in Alzheimer's disease
Uddin, M. S., Yu, W. S., & Lim, L. W. (2021) · Ageing Research Reviews · doi:10.1016/j.arr.2021.101417 · Cited by 118 · see citing works
The activity of early-life gene regulatory elements is hijacked in aging through pervasive AP-1-linked chromatin opening
Patrick, R., Naval-Sánchez, M., Deshpande, N., Huang, Y., Zhang, J., Chen, X., Yang, Y., Tiwari, K., Esmaeili, M., Tran, M., et al. (2024) · Cell Metabolism · doi:10.1016/j.cmet.2024.06.006 · Cited by 73 · see citing works
m6A hypomethylation of DNMT3B regulated by ALKBH5 promotes intervertebral disc degeneration via E4F1 deficiency
Li, G., Luo, R., Zhang, W., He, S., Wang, B., Liang, H., Song, Y., Ke, W., Shi, Y., Feng, X., et al. (2022) · Clinical and Translational Medicine · doi:10.1002/ctm2.765 · Cited by 69 · see citing works
AP ‐1 is a regulatory transcription factor of inflammaging in the murine kidney and liver
Yu, X., Wang, Y., Song, Y., Gao, X., & Deng, H. (2023) · Aging Cell · doi:10.1111/acel.13858 · Cited by 61 · see citing works
Mitochondrial dysfunction and aging: multidimensional mechanisms and therapeutic strategies
Wei, P., Zhang, X., Yan, C., Sun, S., Chen, Z., & Lin, F. (2025) · Biogerontology · doi:10.1007/s10522-025-10273-4 · Cited by 60 · see citing works
“Altered BRG1 expression—via gene silencing or overexpres-sion—induces cellular senescence in human and rat mesenchymal stem cells (MSCs) (Zhang et al. 2021). ncRNA regulation: posttranscriptional control of aging ncRNAs are RNA molecules that do not encode proteins and include ribosomal RNA (rRNA),…”
Self-citation
Integrated Stress Response (ISR) Pathway: Unraveling Its Role in Cellular Senescence
Kalinin, A., Zubkova, E., & Menshikov, M. Y. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms242417423 · Cited by 58 · see citing works
Vascular Endothelial Senescence: Pathobiological Insights, Emerging Long Noncoding RNA Targets, Challenges and Therapeutic Opportunities
Sun, X., & Feinberg, M. W. (2021) · Frontiers in Physiology · doi:10.3389/fphys.2021.693067 · Cited by 55 · see citing works
“…amyloid β 1-42 oligomer (Donnini et al., 2010; Singh Angom et al., 2019), hyperglycemia (Prattichizzo et al., 2018), oxidized LDL, homocysteine (Zhang et al., 2015), and angiotensin II (Yang D. et al., 2019; Khemais-Benkhiat et al., 2020) all can induce or accelerate endothelial cellular…”
Background
Unveiling E2F4, TEAD1 and AP-1 as regulatory transcription factors of the replicative senescence program by multi-omics analysis
Wang, Y., Liu, L., Song, Y., Yu, X., & Deng, H. (2022) · Protein & Cell · doi:10.1007/s13238-021-00894-z · Cited by 52 · see citing works
“Consistent with the results from a previous study (Zhang et al., 2021), we found that knockdown of Atf3 decreased Cdkn2a (p16) expression significantly (Fig.”
Influential
AP-1 activation mediates post-natal cardiomyocyte maturation
Zhang, H., Pei, L., Ouyang, Z., Wang, H., Chen, X., Jiang, K., Huang, S., Jiang, R., Xiang, Y., & Wei, K. (2022) · Cardiovascular Research · doi:10.1093/cvr/cvac088 · Cited by 52 · see citing works
Single-Cell RNA Sequencing and Assay for Transposase-Accessible Chromatin Using Sequencing Reveals Cellular and Molecular Dynamics of Aortic Aging in Mice
Xie, W., Ke, Y., You, Q., Li, J., Chen, L., Li, D., Fang, J., Chen, X., Zhou, Y., Chen, L., et al. (2022) · Arteriosclerosis, Thrombosis, and Vascular Biology · doi:10.1161/atvbaha.121.316883 · Cited by 46 · see citing works
Co-existing TP53 and ARID1A mutations promote aggressive endometrial tumorigenesis
Reske, J. J., Wilson, M. R., Holladay, J., Siwicki, R. A., Skalski, H. J., Harkins, S. K., Adams, M., Risinger, J. I., Hostetter, G. H., Lin, K. Y., et al. (2021) · PLoS Genetics · doi:10.1371/journal.pgen.1009986 · Cited by 44 · see citing works
The sirtuin-associated human senescence program converges on the activation of placenta-specific gene PAPPA
Bi, S., Jiang, X., Ji, Q., Wang, Z., Ren, J., Wang, S., Yu, Y., Wang, R., Liu, Z., Liu, J., et al. (2024) · Developmental Cell · doi:10.1016/j.devcel.2024.02.008 · Cited by 42 · see citing works
Reactivation of senescence-associated endogenous retroviruses by ATF3 drives interferon signaling in aging
Mao, J., Zhang, Q., Zhuang, Y., Zhang, Y., Li, L., Pan, J., Xu, L., Ding, Y., Wang, M., & Cong, Y. (2024) · Nature Aging · doi:10.1038/s43587-024-00745-6 · Cited by 38 · see citing works
“In addition, it was reported that ATF3 regulates cellular senescence by reconstructing accessible chromatin profiles 31 .”
The impact of ageing mechanisms on musculoskeletal system diseases in the elderly
Cai, Y., Han, Z., Cheng, H., Li, H., Wang, K., Chen, J., Liu, Z., Xie, Y., Lin, Y., Zhou, S., et al. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1405621 · Cited by 47 · see citing works
Spurious intragenic transcription is a feature of mammalian cellular senescence and tissue aging
Sen, P., Donahue, G., Li, C. Y., Egervári, G., Yang, N., Lan, Y., Robertson, N., Shah, P. P., Kerkhoven, E., Schultz, D., et al. (2023) · Nature Aging · doi:10.1038/s43587-023-00384-3 · Cited by 37 · see citing works
Senescent Microglia Represent a Subset of Disease-Associated Microglia in P301S Mice
Ng, P. Y., Zhang, C., Li, H., & Baker, D. J. (2023) · Journal of Alzheimer s Disease · doi:10.3233/jad-230109 · Cited by 38 · see citing works
Self-citation
Multiparity increases the risk of diabetes by impairing the proliferative capacity of pancreatic β cells
Moon, J. H., Lee, J., Kim, K. H., Kim, H. J., Kim, H., Cha, H.-N., Park, J., Lee, H. F., Park, S.-Y., Jang, H. C., et al. (2023) · Experimental & Molecular Medicine · doi:10.1038/s12276-023-01100-2 · Cited by 31 · see citing works
Osteocyte ferroptosis induced by ATF3 / TFR1 contributes to cortical bone loss during ageing
Yin, Y., Chen, G., Yang, C., Wang, J., Peng, J., Huang, X., Tang, Q., & Chen, L. (2024) · Cell Proliferation · doi:10.1111/cpr.13657 · Cited by 33 · see citing works
“33 We found that ATF3 binds to the promoter of Tfr1 (Figure 4E) and activates its transcription (Figure 4F).”
BackgroundSelf-citation
Aging insights from heterochronic parabiosis models
Lagunas‐Rangel, F. A. (2024) · npj Aging · doi:10.1038/s41514-024-00166-0 · Cited by 34 · see citing works
“ATF3 and ATF4 play a vital role in inducing speci ﬁ c senescence-associated mRNAs, either by directly acting on their promoters or by modulating chromatin accessibility 76,77 .”
Background
Early response evaluation by single cell signaling profiling in acute myeloid leukemia
Tislevoll, B. S., Hellesøy, M., Fagerholt, O. H. E., Gullaksen, S., Srivastava, A., Birkeland, E., Kleftogiannis, D., Durán, P. A., Piechaczyk, L., Tadele, D. S., et al. (2023) · Nature Communications · doi:10.1038/s41467-022-35624-4 · Cited by 32 · see citing works
Chronological attenuation of NPRA / PKG / AMPK signaling promotes vascular aging and elevates blood pressure
Long, C., Liu, H., Zhan, W., Chen, L., Yu, Z., Tian, S., Yang, X. D., Chen, S., & Tian, X. (2022) · Aging Cell · doi:10.1111/acel.13699 · Cited by 28 · see citing works
“In fact, the published GEO DataSets from microarray (GSE45541)- or RNA sequencing (GSE130727, GSE163251, and GSE17506) reinforced the finding that NPRA is decreased during endothelial cell senescence (Casella et al., 2019; Wong et al., 2017; Zhang et al., 2021).”
BackgroundSelf-citation
Changes of Gene Expression Patterns of Muscle Pathophysiology-Related Transcription Factors During Denervated Muscle Atrophy
Yang, X., Li, M., Ji, Y., Lin, Y., Xu, L., Gu, X., Sun, H., Wang, W., Shen, Y., Liu, H., et al. (2022) · Frontiers in Physiology · doi:10.3389/fphys.2022.923190 · Cited by 28 · see citing works
High-throughput mechanical phenotyping and transcriptomics of single cells
Shiomi, A., Kaneko, T., Nishikawa, K., Tsuchida, A., Isoshima, T., Sato, M., Toyooka, K., Doi, K., Nishikii, H., & Shintaku, H. (2024) · Nature Communications · doi:10.1038/s41467-024-48088-5 · Cited by 24 · see citing works
New Insights into the Genetics and Epigenetics of Aging Plasticity
Zhang, J., Wang, S., & Liu, B. (2023) · Genes · doi:10.3390/genes14020329 · Cited by 23 · see citing works
FOXM1 expression reverts aging chromatin profiles through repression of the senescence-associated pioneer factor AP-1
Ferreira, F. J., Galhardo, M., Nogueira, J. M., Teixeira, J., Logarinho, E., & Bessa, J. (2025) · Nature Communications · doi:10.1038/s41467-025-57503-4 · Cited by 24 · see citing works
“Also, it is concurring with the reported enrichment of AP-1 binding motifs in open chromatin regions of induced senescent cells 14,15 and murine aged cell types 26,27 .”
Influential
Single-Cell Analysis Identify Transcription Factor BACH1 as a Master Regulator Gene in Vascular Cells During Aging
Ge, F., Pan, Q., Qin, Y., Jia, M., Ruan, C., Wei, X., Jing, Q., Zhi, X., Wang, X., Jiang, L., et al. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.786496 · Cited by 21 · see citing works
“In contrast, activating transcription factor 3 (Atf3) activity was high in aged vessels, which has been shown to promote cellular senescence (Zhang et al., 2021).”
Background
Routes of Albumin Overload Toxicity in Renal Tubular Epithelial Cells
Eleftheriadis, T., Pissas, G., Golfinopoulos, S., Efthymiadi, M., Poulianiti, C., Konsta, M. A. P., Liakopoulos, V., & Stefanidis, I. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24119640 · Cited by 21 · see citing works
“The rise of p16 is the result of ATF3 upregulation [45,46].”
Background
Increased matrix stiffness promotes fibrogenesis of hepatic stellate cells through AP-1-induced chromatin priming
Zhao, W., Yuan, W., Dong, T., Qi, W., Feng, Z., Li, C., & Sun, Y. (2025) · Communications Biology · doi:10.1038/s42003-025-08160-2 · Cited by 16 · see citing works
Treating Metabolic Dysregulation and Senescence by Caloric Restriction: Killing Two Birds with One Stone?
Russo, L., Babboni, S., Andreassi, M. G., Daher, J., Canale, P., Turco, S. D., & Basta, G. (2025) · Antioxidants · doi:10.3390/antiox14010099 · Cited by 15 · see citing works
“For instance, in human ECs, transcription factors such as activating transcription factor 3 (a member of the AP-1 family) influence chromatin remodeling, altering gene expression and promoting senescence [120].”
Age-Associated Different Transcriptome Profiling in Zebrafish and Rats: an Insight into the Diversity of Vertebrate Aging
Kijima, Y., Wantong, W., Igarashi, Y., Yoshitake, K., Asakawa, S., Suzuki, Y., Watabe, S., & Kinoshita, S. (2022) · Marine Biotechnology · doi:10.1007/s10126-022-10153-9 · Cited by 14 · see citing works
“1 3 in vitro cell culture studies have reported elevated AP-1 activities in senescent cells; these activities contribute to chromatin remodeling and p21-mediated cellular senescence (Zhang et al. 2021; Kim et al. 2015).”
Background
ATF3 Deficiency Exacerbates Ageing‐Induced Atherosclerosis and Clinical Intervention Strategy
Nie, H., Ji, T., Wan, Z., Huang, J., Li, H., Zou, L., Yang, Z. L., Li, J., Guan, Y., Ruan, L., et al. (2025) · Advanced Science · doi:10.1002/advs.202502249 · Cited by 12 · see citing works
Self-citation
Increased chromatin accessibility underpins senescence
Lopes‐Paciencia, S., & Ferbeyre, G. (2025) · FEBS Journal · doi:10.1111/febs.70136 · Cited by 14 · see citing works
Cellular senescence in human liver under normal aging and cancer
Karpova, A., Li, X., Peng, C.-W., Gallant, K. L., Rapp, D. R., Alligood, D. M., Houston, A. J., Park, A., Targino da Costa, A. L. N., Chou, W.-H., et al. (2026) · Cell Genomics · doi:10.1016/j.xgen.2025.101133 · Cited by 13 · see citing works
A natural variation-based screen in mouse cells reveals USF2 as a regulator of the DNA damage response and cellular senescence
Kang, T., Moore, E. C., Kopania, E. E. K., King, C. D., Schilling, B., Campisi, J., Good, J. M., & Brem, R. B. (2023) · G3: Genes, Genomes, Genetics · doi:10.1093/g3journal/jkad091 · Cited by 10 · see citing works
Resetting the aging clock through epigenetic reprogramming: Insights from natural products
Liu, X., Feng, J. H., Guo, M., Chen, C., Zhao, T., Sun, X., & Zhang, Y. (2025) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2025.108850 · Cited by 9 · see citing works
Activating Transcription Factor 3 (ATF3) Regulates Cellular Senescence and Osteoclastogenesis via STAT3/ERK and p65/AP-1 Pathways in Human Periodontal Ligament Cells
Bae, W.-J., & Lee, S.-I. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26104959 · Cited by 8 · see citing works
“Recent studies highlight ATF3’s role in cellular senescence through chromatin reorganization [13], particularly in cardiac myocytes [14] and macrophages [15].”
TEAD4 antagonizes cellular senescence by remodeling chromatin accessibility at enhancer regions
Zhang, D., Zhu, Y., Ju, Y., Zhang, H., Zou, X., She, S., Zhu, D., & Guan, Y. (2023) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-023-04980-9 · Cited by 8 · see citing works
“…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.”
ResultSelf-citation
Methylmercury-induced DNA methylation—From epidemiological observations to experimental evidence
Cediel-Ulloa, A., Yu, X., Hinojosa, M. G., Johansson, Y., Forsby, A., Bröberg, K., & Rüegg, J. (2022) · Frontiers in Genetics · doi:10.3389/fgene.2022.993387 · Cited by 8 · see citing works
Single-Cell Multiomics Analysis of Early Wound Response Programs in the Mouse Corneal Epithelium
Lu, Z., Ye, J.-G., Li, J.-N., Liang, J.-B., Zhou, M., Hu, Q., Zhang, Q., Lin, Y., & Zheng, Y. (2025) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.66.3.9 · Cited by 8 · see citing works
“46 In the human umbilical vein endothelial cell line, Zhang et al. 56 identified that AP-1 TFs were capable of driving chromatin accessibility reconstruction and regulating senescence.”
Malate dehydrogenase‐2 inhibition shields renal tubular epithelial cells from anoxia‐reoxygenation injury by reducing reactive oxygen species
Pissas, G., Tziastoudi, M., Divani, M., Poulianiti, C., Konsta, M. A. P., Lykotsetas, E., Liakopoulos, V., Stefanidis, I., & Eleftheriadis, T. (2024) · Journal of Biochemical and Molecular Toxicology · doi:10.1002/jbt.23854 · Cited by 7 · see citing works
Sex difference, proteostasis and mitochondrial function impact stroke-related sarcopenia—A systematic review and meta-analysis
Huang, C., & Liu, Y.-H. (2024) · Ageing Research Reviews · doi:10.1016/j.arr.2024.102484 · Cited by 6 · see citing works
The influence of age on cellular senescence in injured versus healthy muscle and its implications on rotator cuff injuries
Wang, K. C., Lau, J., Garcia, S. M., Wague, A., Sharma, S., Liu, X., & Feeley, B. T. (2025) · Journal of Shoulder and Elbow Surgery · doi:10.1016/j.jse.2025.02.008 · Cited by 6 · see citing works
Epigenetic Regulation of Cellular Senescence in Gastrointestinal Cancer
Ye, T., Gao, H., Zhang, Z., Ge, Y., Liu, Y.-K., Yan, J.-Y., Li, D., Chen, F., & Song, H. (2025) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-24-0949 · Cited by 6 · see citing works
DNA methylation dynamics during yak adipocyte differentiation
Zhang, Z., Zhang, Y., Ma, L., Bao, Q., Liang, C., Chu, M., Guo, X., Bao, P., & Yan, P. (2024) · International Journal of Biological Macromolecules · doi:10.1016/j.ijbiomac.2024.129715 · Cited by 6 · see citing works
Imperfect repair in aging: senescent cells and the hepatic fibrotic niche
Kim, J., Kim, M., & Kim, C. (2026) · BMB Reports · doi:10.5483/bmbrep.2025-0224 · Cited by 6 · see citing works
“…a stable senescent state (often characterized by p16 upregulation) through a dynamic interplay of various epigenetic regulators, such as the bromodomain protein BRD4 (16), and the acetyltransferase KAT7 (17), and key transcriptional drivers that include AP − 1 (18), GATA4 (19), and C/EBP  (20).”
Mechanisms and interventions of epigenetic aging
Chu, Q., Li, Y., Wu, Z., Qu, J. T., & Liu, G. (2026) · Cell chemical biology · doi:10.1016/j.chembiol.2026.05.007 · Cited by 4 · see citing works
Dysregulation of endogenous retroviruses triggers aging and senescence
Kreiling, J. A. (2024) · Nature Aging · doi:10.1038/s43587-024-00759-0 · Cited by 4 · see citing works
ATF3 drives cell senescence through TGFβ/Pdcd5 pathway in cardiac myocyte
Huang, Y., Zhang, J., & Yang, J. (2021) · International Journal of Cardiology · doi:10.1016/j.ijcard.2021.11.067 · Cited by 4 · see citing works
Epigenetic regulation of Hutchinson-Gilford progeria syndrome: from molecular mechanisms to targeted interventions
Liu, X., Yang, S., Jiang, J., Dong, S., & Zhang, Y. (2025) · Oral Science and Homeostatic Medicine · doi:10.26599/oshm.2025.9610013 · Cited by 3 · see citing works
Chronic nanoplastics exposure drives lung cancer progression through ATF3/PCK2 axis-mediated rewiring of truncated gluconeogenesis
Li, Q., Meng, W., Xie, C., Wang, F., Deng, Y., Chen, K., Li, Y., Li, Y. H., Wen, Y., Zhu, J., et al. (2025) · Journal of Hazardous Materials · doi:10.1016/j.jhazmat.2025.140764 · Cited by 3 · see citing works
Chromatin accessibility regulates age-dependent nuclear mechanotransduction
Liao, Y., Yuan, L., Sornapudi, T. R., Land, M., Gupta, R., & Shivashankar, G. V. (2026) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2522217123 · Cited by 3 · see citing works
From molecular damage to regulatory constraint: epigenetic and metabolic limits of cellular plasticity in aging
Godlewski, A., & Dziaman, T. (2026) · Frontiers in Aging · doi:10.3389/fragi.2026.1872180 · Cited by 4 · see citing works
“Structural reorganization disrupts mostly intergenic regions, including enhancers (Zhang C. et al., 2021).”
Upregulated CEMIP promotes intervertebral disc degeneration via AP‐1‐mediated change in chromatin accessibility
Shu, S., Zhang, X., Feng, Z., Liu, Z., Wang, K., Li, F., Wu, Y., Shi, B., Qiu, Y., Zhu, Z., et al. (2025) · Clinical and Translational Medicine · doi:10.1002/ctm2.70322 · Cited by 3 · see citing works
“53,57 This underscores the necessity of a deeper exploration of AP-1 family functions, to identify precise intervention targets to counteract degenerative processes, particularly in IDD.”
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Integrated analyses of the single-cell ATAC-seq and RNA-seq reveal the epigenetic landscape of human ovarian agingPreprint
Xu, Y., Chen, J., Gu, S., Liu, Y., Ni, H., Huang, Y. H., Gao, S., Sheng, N., Zhang, X., He, X., et al. (2021) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2021.11.07.467593 · Cited by 3 · see citing works
Self-citation
FOXF1/2 establish a senescence-specific enhancer landscape to activate the pro-inflammatory senescence-associated secretory phenotype
Etoh, K., Hino, Y., Morishita, H., & Nakao, M. (2026) · Molecular Cell · doi:10.1016/j.molcel.2026.03.020 · Cited by 2 · see citing works
Lost in HELLS: Disentangling the mystery of SALNR existence in senescence cellular models
Consiglio, A., Venturin, M., Briguglio, S., Rossi, C., Grillo, G., Bellosta, S., Cattaneo, M. G., Licciulli, F., & Battaglia, C. (2023) · PLoS ONE · doi:10.1371/journal.pone.0286104 · Cited by 2 · see citing works
“GSE157867 SRP282193 SRR13336755, SRR13336757, SRR13336758, SRR13336760 HUVECs 2 senescent vs 2 proliferative 2x150bp (paired) Illumina RNAseq (12)”
Cross‐species signaling pathways analysis inspire animal model selections for drug screening and target prediction in vascular aging diseases
Sun, F., Chen, X., Zhang, S., Jiang, H., Chen, T., Xing, T., Li, X., Sultan, R., Wang, Z., & Jia, J. (2024) · Evolutionary Applications · doi:10.1111/eva.13708 · Cited by 2 · see citing works
Identification of Regulatory Elements in Primary Sensory Neurons Involved in Trauma-Induced Neuropathic Pain
Stephens, K., Moore, C., Vinson, D. A., White, B. E., Renfro, Z. T., Zhou, W., Ji, Z., Ji, H., Zhu, H., Guan, Y., et al. (2023) · Molecular Neurobiology · doi:10.1007/s12035-023-03673-5 · Cited by 1 · see citing works
“Inter-estingly, ATF3 can drive increased chromatin accessibility at distal regulatory elements in human umbilical vein endothelial cells [19].”
BackgroundSelf-citation
Liquid Guardians: Biomolecular Condensates Shield Heterochromatin Against Cellular Senescence
Xie, J., & Han, Z. (2025) · BioEssays · doi:10.1002/bies.70026 · Cited by 1 · see citing works
“A prominent example is ATF3, an AP-1 family transcription factors that promotes cellular senescence by remodeling chromatin accessibility [145].”
Integrated epigenetic networks in aging: from histone to RNA modifications
Wang, X., 朱秋楠, Liu, J., Fu, Y., Xu, J., Dong, Z., Tang, B., & Li, J. (2026) · Journal of Translational Medicine · doi:10.1186/s12967-026-07990-w · Cited by 1 · see citing works
“It is critical for reconstructing chromatin accessibility to promote cellular senescence in aging human umbilical vein endothelial cells (HUVEC) [87].”
From systemic disease to the eye: Why senescence deserves attention in ocular infections
Maiti, S., & Joseph, J. (2026) · Experimental Eye Research · doi:10.1016/j.exer.2026.111095 · Cited by 1 · see citing works
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 · see citing works
Transcriptomic analysis of cellular senescence induced by ectopic expression of ATF6α in human breast cancer cells
Kim, J. W., Bae, S.-H., Moon, Y., Kim, E. K., Kim, Y.-J., Park, Y. G., Han, M.-R., & Sohn, J. (2024) · PLoS ONE · doi:10.1371/journal.pone.0309749 · Cited by 1 · see citing works
Age-dependent transcriptional and epigenetic alterations in mouse hepatocytes
Sharma, A. (2021) · doi:10.32657/10356/155390
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
Identification of regulatory elements in primary sensory neurons involved in neuropathic painPreprint
Stephens, K., Moore, C. D., Vinson, D. A., White, B. E., Renfro, Z. T., Zhou, W., Ji, Z., Ji, H., Zhu, H., Guan, Y., et al. (2022) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2022.09.09.507328
Self-citation
JUN upregulation drives aberrant transposable element mobilization, associated innate immune response, and impaired neurogenesis in Alzheimer’s diseasePreprint
Scopa, C., Barnada, S. M., Cicardi, M. E., Singer, M., Trotti, D., & Trizzino, M. (2022) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2022.11.24.517794
Lost in HELLS : disentangling the mystery of SALNR existence in senescence cellular modelsPreprint
Consiglio, A., Venturin, M., Briguglio, S., Rossi, C., Grillo, G., Bellosta, S., Cattaneo, M. G., Licciulli, F., & Battaglia, C. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.02.03.526712
Monocyte subpopulations exhibit distinct TNF-dependent aging signaturesPreprint
Bentz, A. W., Gutierrez, M. A., Loukov, D., Eckman, B., Gadhvi, G. T., Cuda, C. M., Bowdish, D. M. E., & Winter, D. R. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.11.17.567601
Signaling pathways, tumors, senescence and developmental <?A3B2 pi6?>processes associated with AP-1 family
Li, R., Yu, R., & Du, P. (2025) · Scientia Sinica Vitae · doi:10.1360/ssv-2024-0286
The immunological age prediction of monocytes indicates that gestational diabetes mellitus accelerates the aging of monocytes in offspring
Zhang, Y., Guo, R. J., Yin, M., Shi, M., Zhong, T., Liu, S., & Li, X. (2025) · Immunity & Ageing · doi:10.1186/s12979-025-00513-z
“Machine learning techniques are used to estimate cell age and develop predictive models of immune cell aging based on environmental factors [23–27].”
ICE: An imputation framework for detecting cellular senescence using weak single-cell signaturesPreprint
Xu, P., Zhang, H., Zhu, S., & Kong, Y. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.05.25.656048
“ATF3 also remodels chromatin accessibility to promote senescence in endothelial cells and aging tissues, underscoring its pleiotropic role in aging[14, 15].”
ICE: robust detection of cellular senescence from weak single-cell signatures using imputation-based marker refinement
Xu, P., Zhang, H., Zhu, S., & Kong, Y. (2026) · Genome biology · doi:10.1186/s13059-026-03997-0
Stress-responsive enhancer RNAs couple chromatin reprogramming to post-transcriptional control of senescencePreprint
Kuklinkova, R., Benova, N., Kohli, J. S., Boyne, J. R., Roberts, W., & Anene, C. A. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.03.20.713302
“We traced repression of EN526 during senescence upstream of AT hook and bZIP TFs, a class of factors known to respond to cellular stress and implicated in apoptosis, inflammation, and chromatin regulation in senescence 46–48 .”
Transcriptional regulation in cardiovascular aging
Fan, Y., Song, C., Feng, F., Xun, Q., Lu, Y., & Li, C. (2026) · Frontiers in Cardiovascular Medicine · doi:10.3389/fcvm.2026.1752877
Reverse aging through redox-sensitive transcription factors modulation
Kostenko, V., Akimov, O., Kostenko, H., Рябушко, Р. М., & Kostenko, V. (2026) · Elsevier eBooks · doi:10.1016/b978-0-443-33159-6.00006-0
Bioinformatics Re-analysis of murine transcriptomic datasets identifies SASP and MAPK/NF-κB signaling pathways in noise-accelerated cochlear aging
Zhang, G., Ren, D., & Wang, S. (2026) · Hearing Research · doi:10.1016/j.heares.2026.109679
Intracellular Calcium Overload Promotes NFATc1-ATF3 Activation and Induces the Senescence-Associated Phenotype in Irradiated Osteocytes
Han, H., Zhao, F., Wang, J., et al. (2026) · Life · doi:10.3390/life16060984
“…loci, including CD44, where it recruits histone acetyltransferases to deposit H3K27ac marks, thereby promoting chromatin relaxation, transcriptional activation, and the establishment of senescence programs; this leads to robust induction of p16 INK4a and elevated SA-β -gal activity [48].”
SenFlag gene signature identifies senescent cells in mouse and human tissues through a conserved core transcriptional program
Altulea, A., Mackedenski, S. J., Nehme, J., & Demaria, M. (2026) · The EMBO Journal · doi:10.1038/s44318-026-00845-6 · Cited by 1 · see citing works
Activating Transcription Factor 3 in Pain: A Molecular Regulator and Emerging Biomarker
García-Domínguez, M. (2026) · Genes · doi:10.3390/genes17091034
“Histone methylation also contributes to ATF3 regulation, with active chromatin marks (H3K4me3) being associated with transcriptional activation, whereas repressive marks including H3K27me3 are associated with transcriptional silencing under basal conditions [79–81].”
A transitional senescence program drives inflammatory monocyte state expansion in aging humansPreprint
Vasilopoulos, T., Turano, P. S., Garza‐Martinez, L., Akbulut, E., Konda, M., Herbig, U., Fitzgerald-Bocarsly, P. A., & Martínez‐Zamudio, R. I. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.09.09.750459

Authors: Zhang, C., Zhang, X., Huang, L., Guan, Y., Huang, X., Tian, X., Zhang, L., & Tao, W.
Affiliations: Peking University (CN)
Nanchang University (CN)
Corresponding author: Tao, Wei
ORCID: Zhang, Chao
Zhang, Xuebin
Huang, Li
Guan, Yiting
Huang, Xiaoke
Tian, Xiao‐Li
Zhang, Lijun
Tao, Wei
Venue: Aging Cell
Publisher: Wiley
Published: 2021-02-04
Volume: 20
Issue: 3
Pages: e13315-e13315
ISSN: 1474-9718 (ISSN-L)
1474-9726
DOI: 10.1111/acel.13315
PMC: PMC7963335
OpenAlex: W3127751237
Semantic Scholar: 8ade0fee16220a50ac020f410fc7b2776a1a50aa
Cited by: 84
References: 105
Citations by year: 2026: 17 · 2025: 18 · 2024: 13 · 2023: 14 · 2022: 14 · 2021: 8
FWCI: 3.85
Type: journal article
Language: en
Open access: gold
doi.org
Licence: cc-by
creativecommons.org/licenses/by/4.0/ (vor)
Locations: Aging Cell (publishedVersion, cc-by)
bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
PubMed Central (publishedVersion, cc-by)
PubMed (publishedVersion)
Funders: National Natural Science Foundation of China (2020YFC2002903, 31871312, 31471205, 31671426)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
Keywords: ATF3, cellular senescence, chromatin accessibility, chromatin organization, AP-1 transcription factor, enhancers, DNA methylation, gene regulatory networks, human umbilical vein endothelial cells, gene expression reprogramming
MeSH terms: Chromatin, Gene Expression Regulation, Humans, Transcription, Genetic, Genome, Human, Cellular Senescence, Transcription Factor AP-1, DNA Methylation, Activating Transcription Factor 3, Gene Regulatory Networks, HEK293 Cells, Human Umbilical Vein Endothelial Cells

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ATF3 drives senescence by reconstructing accessible chromatin profiles

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