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BRD4 Connects Enhancer Remodeling to Senescence Immune Surveillance
Open accessPublished version of a preprint
Abstract
Oncogene-induced senescence is a potent barrier to tumorigenesis that limits cellular expansion following certain oncogenic events. Senescent cells display a repressive chromatin configuration thought to stably silence proliferation-promoting genes while simultaneously activating an unusual form of immune surveillance involving a secretory program referred to as the senescence-associated secretory phenotype (SASP). Here, we demonstrate that senescence also involves a global remodeling of the enhancer landscape with recruitment of the chromatin reader BRD4 to newly activated super-enhancers adjacent to key SASP genes. Transcriptional profiling and functional studies indicate that BRD4 is required for the SASP and downstream paracrine signaling. Consequently, BRD4 inhibition disrupts immune cell–mediated targeting and elimination of premalignant senescent cells in vitro and in vivo. Our results identify a critical role for BRD4-bound super-enhancers in senescence immune surveillance and in the proper execution of a tumor-suppressive program. Significance: This study reveals how cells undergoing oncogene-induced senescence acquire a distinctive enhancer landscape that includes formation of super-enhancers adjacent to immune-modulatory genes required for paracrine immune activation. This process links BRD4 and super-enhancers to a tumor-suppressive immune surveillance program that can be disrupted by small molecule inhibitors of the bromo and extra terminal domain family of proteins. Cancer Discov; 6(6); 612–29. ©2016 AACR. See related commentary by Vizioli and Adams, p. 576. This article is highlighted in the In This Issue feature, p. 561
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“Genome-wide analysis of H3 Lys4 trimethylation, H3 Lys27 trimethylation and H3 Lys27 acetylation in senescent cells has also revealed the dynamic acquisition and depletion of large-scale chromatin domains that have been proposed to regulate the expression of key senescence downstream effectors68–72”
From Cellular senescence in ageing: from mechanisms to therapeutic opportunities (2021) · cites this paper as [71]
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“BRD4 contributes to the proper execution of cellular senescence and acts, unexpectedly, as a tumour suppressor.”
From Cellular senescence in ageing: from mechanisms to therapeutic opportunities (2021) · cites this paper as [71]
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“Indeed, chemical and genetic inactivation of BRD4 blunts the SASP, limits OIS immune-mediated cell clearance and may thus fail to remove damaged cells that are prone to senescence escape71.”
From Cellular senescence in ageing: from mechanisms to therapeutic opportunities (2021) · cites this paper as [71]
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“Other epigenetic regulators, such as macroH2A1, high mobility group box 2 (HMGB2), mixed‐lineage leukemia 1 (MLL1) and bromodomain‐containing protein 4 (BRD4), have been demonstrated as regulators of SASP factor gene expression in response to DNA damage.52, 53, 54, 55”
From Cellular senescence and senescence-associated secretory phenotype via the cGAS-STING signaling pathway in cancer (2020) · cites this paper as [55]
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In the citing paper
“BRD4 inactivation via shRNA or BET inhibitors has been shown to repress SASP gene expression in oncogene-induced senescent cells [29], suggesting the possibility of senescence without the SASP [30].”
From Ensemble of Time-Evolving SASP Gene Sets Identifies IGFBP7 and CDKN1A as a Potential Marker Pair for Senescent Fibroblast Subpopulations Across Tissues (2026) · cites this paper as [29]
In the citing paper
“Other epigenetic regulators such as BRD4 (Tasdemir et al., 2016), MLL1 (Capell et al., 2016), HMGB2 (Guerrero and Gil, 2016), histone variant macroH2A1 (Chen et al., 2015), and GATA4 (Kang et al., 2015) are also involved in regulating SASP.”
From Mechanisms of Cellular Senescence: Cell Cycle Arrest and Senescence Associated Secretory Phenotype (2021) · cites this paper as Tasdemir et al., 2016
In the citing paper
“The SASP is thought to instigate immune clearance of the damaged/stressed cells (Tasdemir et al., 2016), but the immediate negative consequence is the potential to drive local tissue damage and systemic chronic sterile inflammation (Franceschi and Campisi, 2014).”
From DNA damage-how and why we age? (2021) · cites this paper as Tasdemir et al., 2016
In the citing paper
“More directly, the chromatin reader BRD4 is recruited to super-enhancer elements that form adjacent to key SASP genes and is required for their expression [170].”
From Mechanisms and Regulation of Cellular Senescence (2021) · cites this paper as [170]
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Citations
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InfluentialSuper-enhancers in the control of cell identity and disease
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InfluentialSelective Inhibition of Tumor Oncogenes by Disruption of Super-Enhancers
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“BRD4 Is Recruited to Senescence-Activated SEs Associated with Key SASP Genes One of the proteins that bind acetylated histones at enhancers and are enriched in SEs is the transcriptional coactivator BRD4, which couples enhancer remodeling to RNA Pol II elongation (39).”
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BackgroundA Molecular Switch between Mammalian MLL Complexes Dictates Response to Menin–MLL Inhibition
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“During cellular senescence, super-enhancers characterized by H3K27 acetylation are formed in the vicinity of SASP factor genes such as IL1A and IL1B (46) .”
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“89 These findings collectively suggest that SASP induction is subject to regulation through epigenetic changes occurring in senescent cells.”
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“It is well-noted that epigenome changes dramatically during senescence and multiple epigenetic modulators are involved, such as BRD4 and MLL1 [66, 67].”
BackgroundEscape from oncogene-induced senescence is controlled by POU2F2 and memorized by chromatin scars
Martínez‐Zamudio, R. I., Stefa, A., de Freitas, J. A. N. L. F., Vasilopoulos, T., Simpson, M., Doré, G. R. G., Roux, P., Galan, M. A., Chokshi, R. J., Bischof, O., et al. (2023) · Cell Genomics · doi:10.1016/j.xgen.2023.100293 · Cited by 47
DNA Methylation Changes and Inflammaging in Aging-Associated Diseases
Alimohammadi, M., Makaremi, S., Rahimi, A. A. R., Asghariazar, V., Taghadosi, M., & Safarzadeh, E. (2022) · Epigenomics · doi:10.2217/epi-2022-0143 · Cited by 44
Thompson, P. J., Shah, A. N., Apostolopolou, C.-C., & Bhushan, A. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20194776 · Cited by 43
“Inhibition of BRD4 in human fibroblasts after the induction of senescence also inhibits activation of SASP [8], consistent with our findings in human Figure 4.”
BackgroundResultInfluentialXu, Y.-D., Liang, X., Li, Z., Wu, Z., Yang, J., Jia, S.-Z., Peng, R., Li, Z., Wang, X.-H., Luo, F., et al. (2024) · Biomaterials · doi:10.1016/j.biomaterials.2024.122483 · Cited by 43
Convergent roles of ATF3 and CSL in chromatin control of cancer-associated fibroblast activation
Kim, D., Procopio, M.-G., Ghosh, S., Jo, S., Goruppi, S., Magliozzi, F., Bordignon, P., Neel, V., Angelino, P., & Dotto, G. P. (2017) · The Journal of Experimental Medicine · doi:10.1084/jem.20170724 · Cited by 43
“It was recently reported that in the context of fibrotic conversion of liver stellate cells (Ding et al., 2015) or ras oncogene–induced senescence (Tasdemir et al., 2016), Brd4 silencing exerted the same effects as the BET inhibitors.”
BackgroundGenome-Protecting Compounds as Potential Geroprotectors
Proshkina, E., Shaposhnikov, M. V., & Moskalev, A. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21124484 · Cited by 42
Integrated multi-omics approach revealed cellular senescence landscape
Song, Q., Hou, Y., Zhang, Y., Liu, J., Wang, Y., Fu, J., Zhang, C., Cao, M., Cui, Y., Zhang, X., et al. (2022) · Nucleic Acids Research · doi:10.1093/nar/gkac885 · Cited by 44
“We obtained OIS cells’ ChIP-seq data of H3K27ac from GSM2774996, GSM2774997, GSM2774998, GSM2774999, GSM1915115 and GSM2098178, employed control from GSM2774992, GSM2774993, GSM2774994, GSM2774995, GSM1915113, and GSM2098176 (12,35).”
Converging Paths of Pulmonary Arterial Hypertension and Cellular Senescence
van der Feen, D. E., Berger, R. M. F., & Bartelds, B. (2019) · American Journal of Respiratory Cell and Molecular Biology · doi:10.1165/rcmb.2018-0329tr · Cited by 38
The Role of Ageing and Parenchymal Senescence on Macrophage Function and Fibrosis
Campbell, R., Docherty, M.-H., Ferenbach, D. A., & Mylonas, K. J. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.700790 · Cited by 41
“In vitro experiments also showed that conditioned medium from senescent cell cultures induced senescence in naïve cells, halting proliferation and upregulating SA-b-Gal activity, whereas conditioned medium from BRD4inhibited cultures had significantly reduced capacity to transmit senescence to naïve cells (62).”
BackgroundRedmer, T., Raigel, M., Sternberg, C., Ziegler, R., Probst, C., Lindner, D., Aufinger, A., Limberger, T., Trachtová, K., Kodajova, P., et al. (2024) · Molecular Cancer · doi:10.1186/s12943-024-02022-x · Cited by 39
“This was evidenced by the association of the chromatin reader BRD4 with recruitment to enhancer regions activating SASP genes in senescent cells [65].”
BackgroundSenescence of Tumor Cells in Anticancer Therapy—Beneficial and Detrimental Effects
Piskorz, W. M., & Cechowska‐Pasko, M. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms231911082 · Cited by 39
Aging-associated lncRNAs are evolutionarily conserved and participate in NFκB signaling
Cai, D., & Han, J. J. (2021) · Nature Aging · doi:10.1038/s43587-021-00056-0 · Cited by 37
Cellular Senescence in Obesity and Associated Complications: a New Therapeutic Target
Narasimhan, A., Flores, R. R., Camell, C. D., Bernlohr, D., Robbins, P. D., & Niedernhofer, L. J. (2022) · Current Diabetes Reports · doi:10.1007/s11892-022-01493-w · Cited by 40
“The JAK-STAT3 pathway [25], mTOR pathway [26], bromodomain-containing protein 4 (BRD4) [27], NOTCH1 activity [28], and HMGB proteins [29, 30] are also reported to modulate the composition of SASP with HMGB1 being secreted by SnCs are part of the SASP.”
BackgroundBeyond SAHF: An integrative view of chromatin compartmentalization during senescence
Olan, I., Handa, T., & Narita, M. (2023) · Current Opinion in Cell Biology · doi:10.1016/j.ceb.2023.102206 · Cited by 44
Recent advances in senescence-associated secretory phenotype and osteoporosis
Fan, H., Qiao, Z., Li, J., Shang, G., Shang, C., Chen, S., Leng, Z., Su, H., Kou, H., & Liu, H. (2024) · Heliyon · doi:10.1016/j.heliyon.2024.e25538 · Cited by 42
Epigenetic dysregulation in cardiovascular aging and disease
Herman, A. B., Occean, J. R., & Sen, P. (2021) · The Journal of Cardiovascular Aging · doi:10.20517/jca.2021.16 · Cited by 39
Aging tumour cells to cure cancer: “pro-senescence” therapy for cancer
Calcinotto, A., & Alimonti, A. (2017) · Swiss Medical Weekly · doi:10.57187/smw.2017.14367 · Cited by 42
Mamun, A. A., Sufian, M. A., Uddin, M. S., Sumsuzzman, D. M., Jeandet, P., Islam, M. S., Zhang, H., Kong, A. T., & Sarwar, M. S. (2022) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2022.174991 · Cited by 35
Titration of RAS alters senescent state and influences tumour initiation
Chan, A. S. L., Zhu, H., Narita, M., Cassidy, L. D., Young, A. R. J., Bermejo‐Rodríguez, C., Janowska, A. T., Chen, H., Gough, S., Oshimori, N., et al. (2024) · Nature · doi:10.1038/s41586-024-07797-z · Cited by 38
A novel ROR1-targeting antibody-PROTAC conjugate promotes BRD4 degradation for solid tumor treatment
Wang, L., Ke, Y., He, Q., Paerhati, P., Zhuang, W., Yue, Y., Liu, J., Zhang, J., Huang, L., Yin, Q., et al. (2024) · Theranostics · doi:10.7150/thno.102531 · Cited by 38
HSF1 Stimulates Glutamine Transport by Super-Enhancer-Driven lncRNA LINC00857 in Colorectal Cancer
Shen, Q., Wang, R., Liu, X., Song, P., Zheng, M., Ren, X., Ma, J., Lü, Z., & Li, J. (2022) · Cancers · doi:10.3390/cancers14163855 · Cited by 33
“The bromodomain and extra-terminal (BET) proteins such as BRD4 serve as primary epigenetic “readers” that activate gene transcription by identifying and binding histone acetylated lysine residues at the region where the super enhancer is located [8,9].”
BackgroundSun, J., Gui, Y., Zhou, S., & Zheng, X. (2023) · Journal of Advanced Research · doi:10.1016/j.jare.2023.11.006 · Cited by 38
“Furthermore, this study high-lighted the necessity of BRD4 binding to SEs for SASP-related gene expression and subsequent paracrine signaling in senescent instead of quiescent cells; genetic deletion or pharmacological inhibition of BRD4 collapses SASP-related gene expression [64].”
Giorgio, E. D., Ranzino, L., Tolotto, V., Dalla, E., Burelli, M., Gualandi, N., & Brancolini, C. (2024) · Cell Death and Disease · doi:10.1038/s41419-024-06548-2 · Cited by 32
“This reorganization involves the restructuring of proximal and distal regulatory elements (promoters and enhancers) with the stabilization of new super-enhancers (SEs) [7 – 9].”
HMGB2 holds the key to the senescence-associated secretory phenotype
Guerrero, A., & Gil, J. (2016) · Journal of Cell Biology · doi:10.1083/jcb.201610044 · Cited by 30
Super-enhancers and novel therapeutic targets in colorectal cancer
Liu, Q., Guo, L., Lou, Z., Xiang, X., & Shao, J. (2022) · Cell Death and Disease · doi:10.1038/s41419-022-04673-4 · Cited by 31
Shigeta, S., Lui, G. Y. L., Shaw, R. C., Moser, R. D., Gurley, K. E., Durenberger, G., Rosati, R., Diaz, R. L., Ince, T. A., Swisher, E. M., et al. (2021) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-20-0809 · Cited by 29
“RNA-sequencing indicates BRD2, BRD3, and BRD4 are all involved in PI3K–AKT signaling BRD4 is known to regulate several important cancer promoting signals such as those downstream of MYC, NFkB, and senescenceassociated secretory phenotypes (15, 37).”
BackgroundImmunomodulatory effects of exercise in cancer prevention and adjuvant therapy: a narrative review
Lyu, D. (2024) · Frontiers in Physiology · doi:10.3389/fphys.2023.1292580 · Cited by 31
Zhang, H., Gui, T., Liu, R., Tong, K., Wu, C., Li, Z., Huang, X., Xu, Q., Yang, J., Tang, W., et al. (2021) · Cell Death and Disease · doi:10.1038/s41419-021-03416-1 · Cited by 36
The Power Behind the Throne: Senescence and the Hallmarks of Cancer
Hoare, M., & Narita, M. (2017) · Annual Review of Cancer Biology · doi:10.1146/annurev-cancerbio-030617-050352 · Cited by 33
Apoptosis signal-regulating kinase 1 promotes inflammation in senescence and aging
Odawara, T., Yamauchi, S., & Ichijo, H. (2024) · Communications Biology · doi:10.1038/s42003-024-06386-0 · Cited by 30
“In this experimental model, increased CCL2 expression in NRAS G12V -expressing hepatocytes was shown to promote macrophage recruitment 4,5,34 .”
Conserved epigenetic hallmarks of T cell aging during immunity and malignancy
Tian, M., Soerens, A. G., Alli, S., Kang, T. G., Vasandan, A. B., Wang, Z., Vezys, V., Kimura, S., Iacobucci, I., Baylin, S. B., et al. (2024) · Nature Aging · doi:10.1038/s43587-024-00649-5 · Cited by 32
“Letter https://doi.org/10.1038/s43587-024-00649-5 To further assess our T cell age epigenetic signature for genes associated with replicative senescence, we next cross-referenced our DMR gene list with published oncogene-induced senescence (OIS)-specific regulatory elements 28 .”
InfluentialEtoh, K., Araki, H., Koga, T., Hino, Y., Kuribayashi, K., Hino, S., & Nakao, M. (2024) · Cell Reports · doi:10.1016/j.celrep.2024.114496 · Cited by 31
Hallmarks of aging: A user’s guide for comparative biologists
Biga, P. R., Duan, J. E., Young, T. E., Marks, J. R., Bronikowski, A. M., Decena-Segarra, L. P., Randolph, E. C., Pavuluri, A., Li, G., Fang, Y., et al. (2024) · Ageing Research Reviews · doi:10.1016/j.arr.2024.102616 · Cited by 33
“The SASP is a dynamic and complex phenomenon that involves the activation of multiple signaling cascades and transcription factors, including NF-κ B (Chien et al., 2011), c/EBP β (Salotti and Johnson, 2019), p38/MAPK (Freund et al., 2011), JAK2/STAT3 (Xu et al., 2015), cGAS-STING pathway (Glück et al., 2017), phosphoi…”
Wang, H., Yu, Y., Li, R., Zhang, H., Chen, Z., Sun, C., & Zhuang, J. (2025) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2025.07.022 · Cited by 36
“For example, while SASP inhibitors effectively suppress SASP at low doses, high doses could lead to the dissolution of senescent cells, resulting in negative consequences 188,189 .”
Super enhancers—Functional cores under the 3D genome
Zhang, J., Yue, W., Zhou, Y., Liao, M., Chen, X., & Hua, J. (2020) · Cell Proliferation · doi:10.1111/cpr.12970 · Cited by 25
“52,53 Super enhancers are very sensitive to histone modification.”
BRD4 inhibitor GNE987 exerts anti-cancer effects by targeting super-enhancers in neuroblastoma
Chen, Y., Li, X., Li, G. L., Tao, Y., Zhuo, R., Cao, H., Jiao, W., Li, Z., Zhu, Z., Fang, F., et al. (2022) · Cell & Bioscience · doi:10.1186/s13578-022-00769-8 · Cited by 29
Gégonne, A., Chen, Q., Dey, A., Etzensperger, R., Tai, X., Singer, A., Meerzaman, D. M., Ozato, K., & Singer, D. S. (2018) · Cell Reports · doi:10.1016/j.celrep.2018.06.007 · Cited by 28
Chromatin-informed inference of transcriptional programs in gynecologic and basal breast cancers
Osmanbeyoglu, H. U., Shimizu, F., Rynne‐Vidal, Á., Alonso‐Curbelo, D., Chen, H.-A., Wen, H. Y., Yeung, T.-L., Jelinic, P., Razavi, P., Lowe, S. W., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-12291-6 · Cited by 26
Self-citationWang, J., Zhou, X., Yu, P., Yao, J., Guo, P., Xu, Q., Zhao, Y., Wang, G., Li, Q., Zhu, X., et al. (2025) · Nature Aging · doi:10.1038/s43587-025-00886-2 · Cited by 28
Dhulkifle, H., Diab, M., Algonaiah, M. A., Korashy, H. M., & Maayah, Z. H. (2024) · ACS Pharmacology & Translational Science · doi:10.1021/acsptsci.3c00219 · Cited by 29
Grosse, L., & Bulavin, D. V. (2020) · Aging · doi:10.18632/aging.103492 · Cited by 27
“encoded at the enhancer level [66, 67] and that the enhancer landscape is dynamically reshaped at each step of the senescence transition [68].”
BackgroundEpigenetic enzymes: A role in aging and prospects for pharmacological targeting
PASYUKOVA, E. G., Symonenko, A. V., Rybina, O. Y., & Vaiserman, A. M. (2021) · Ageing Research Reviews · doi:10.1016/j.arr.2021.101312 · Cited by 28
Counteracting Immunosenescence—Which Therapeutic Strategies Are Promising?
Hieber, C., Grabbe, S., & Bros, M. (2023) · Biomolecules · doi:10.3390/biom13071085 · Cited by 30
Targeting complexes of super‑enhancers is a promising strategy for cancer therapy (Review)
Zheng, C., Liu, M., & Fan, H. (2020) · Oncology Letters · doi:10.3892/ol.2020.11855 · Cited by 27
“At present, the small‐molecule inhibitors designed for cancer treatments include the following three types: i) CDK7 inhibitor (THZ1); ii) BRD4 inhibitor (JQ1); and iii) other inhibitors, which are summarized in Table I (8,21,29,35,39,45-77).”
BackgroundLocus-specific induction of gene expression from heterochromatin loci during cellular senescence
Tomimatsu, K., Bihary, D., Olan, I., Parry, A. J., Schoenfelder, S., Chan, A. S. L., Slater, G. S. C., Ito, Y., Rugg-Gunn, P. J., Kirschner, K., et al. (2021) · Nature Aging · doi:10.1038/s43587-021-00147-y · Cited by 25
Zhang, Y., Song, C., Zhang, Y., Wang, Y., Feng, C., Chen, J., Wei, L., Pan, Q., Shang, D., Zhu, Y., et al. (2021) · Nucleic Acids Research · doi:10.1093/nar/gkab950 · Cited by 24
“For example, the TcoF Bromodomain Containing 4 (BRD4) recruits many enhancers and super-enhancers, while its inhibition can suppress the transcription level of super-enhancers and enhancers associated genes (9,10).”
Background
Metadata
- Authors
- 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., Fennell, M., Thapar, V., Chicas, A., Vakoc, C. R., & Lowe, S. W.
- Affiliations
- Memorial Sloan Kettering Cancer Center (US)
- Cold Spring Harbor Laboratory (US)
- 1Memorial Sloan Kettering Cancer Center, New York, New York.
- Stony Brook University (US)
- Corresponding author
- Vakoc, Christopher R.
- Lowe, Scott W.
- ORCID
- Venue
- Cancer Discovery
- Published
- 2016-06-01
- Volume
- 6
- Issue
- 6
- Pages
- 612-629
- ISSN
- 2159-8274 (ISSN-L)
- 2159-8290
- PMC
- PMC4893996
- OpenAlex
- W2342055991
- Cited by
- 415
- References
- 78
- Citations by year
- 2026: 42 · 2025: 41 · 2024: 62 · 2023: 44 · 2022: 51 · 2021: 49 · 2020: 36 · 2019: 34 · 2018: 20 · 2017: 28 · 2016: 8
- FWCI
- 24.15
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Cancer Discovery (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Cold Spring Harbor Laboratory Institutional Repository (Cold Spring Harbor Laboratory) (submittedVersion)
- Swinburne figshare (Swinburne University of Technology) (submittedVersion)
- Funders
- National Institutes of Health (1s10od020122-01, 5p30ca045508-35)
- National Institute on Aging (R56AG016379, R01AG016379)
- National Cancer Institute (P30-CA045508, R01CA174793, P01CA013106, P30CA008748)
- 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 › Molecular Biology › Chromatin Remodeling and Cancer
- Keywords
- BRD4, super-enhancers, enhancer remodeling, oncogene-induced senescence, senescence-associated secretory phenotype, chromatin reader proteins, paracrine signaling, tumor suppression, senescent cell elimination
- MeSH terms
- Bromodomain Containing Proteins, Animals, Binding Sites, Cell Cycle, Enhancer Elements, Genetic, Fibroblasts, Gene Expression Regulation, Histones, Humans, Immunologic Surveillance, Membrane Proteins, Nuclear Proteins, Oncogenes, Protein Binding, Transcription Factors, Cluster Analysis, Cellular Senescence, Cell Cycle Proteins, Computational Biology, Paracrine Communication, GTP Phosphohydrolases, Gene Expression Profiling, Hepatocytes, Chromatin Assembly and Disassembly, Cell Line, Tumor, Chromatin Immunoprecipitation, Cell Proliferation, Mice, Position-Specific Scoring Matrices, High-Throughput Nucleotide Sequencing, Nucleotide Motifs
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