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BRD4 Connects Enhancer Remodeling to Senescence Immune Surveillance
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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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“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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Self-citation
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Sorted by citations
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“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].”
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Backgroundp21 produces a bioactive secretome that places stressed cells under immunosurveillance
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“However, the recent finding that bromodomain-containing protein 4 inhibition interferes with immune cell–mediated targeting and elimination of senescent cells points to the possibility to combat SASP more specifically.(148)”
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“The DNA damage response induces inflammation and senescence by inhibiting autophagy of GATA4.”
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BackgroundMethodInfluentialSelf-citationClassical and Nonclassical Intercellular Communication in Senescence and Ageing
Fafián‐Labora, J., & O’Loghlen, A. (2020) · Trends in Cell Biology · doi:10.1016/j.tcb.2020.05.003 · Cited by 244
Senescent alveolar macrophages promote early-stage lung tumorigenesis
Prieto, L. I., Sturmlechner, I., Graves, S. I., Zhang, C., Goplen, N. P., Yi, E. S., Sun, J., Li, H., & Baker, D. J. (2023) · Cancer Cell · doi:10.1016/j.ccell.2023.05.006 · Cited by 212
NKG2D-CAR T cells eliminate senescent cells in aged mice and nonhuman primates
Yang, D., Sun, B., Li, S., Wei, W., Liu, X., Cui, X., Zhang, X., Liu, N., Yan, L., Deng, Y., et al. (2023) · Science Translational Medicine · doi:10.1126/scitranslmed.add1951 · Cited by 217
“The human lung fibroblast cell lines IMR90 (catalog number CCL186) and WI38 (catalog number CCL-75) were purchased from the American Type Culture Collection (ATCC), and the HEL1 cell line was purchased from the China Infrastructure of Cell Line Resources (catalog number KCB 86024).”
MethodInfluentialSASP: Tumor Suppressor or Promoter? Yes!
Rao, S. G., & Jackson, J. G. (2016) · Trends in Cancer · doi:10.1016/j.trecan.2016.10.001 · Cited by 206
A BET family protein degrader provokes senolysis by targeting NHEJ and autophagy in senescent cells
Wakita, M., Takahashi, A., Sano, O., Loo, T. M., Imai, Y., Narukawa, M., Iwata, H., Matsudaira, T., Kawamoto, S., Ohtani, N., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-15719-6 · Cited by 206
Strategies targeting cellular senescence
Ovadya, Y., & Krizhanovsky, V. (2018) · Journal of Clinical Investigation · doi:10.1172/jci95149 · Cited by 200
“The solution to this problem might come from new studies on epigenetic regulators, including mixed-lineage leukemia protein 1 (MLL1), bromodomain-containing protein 4 (BRD4), and high-mobility group box 2 (HMGB2), which are responsible for reshaping the epigenetic landscape of senescent cells in a manner that would di…”
BackgroundRoles of extracellular vesicles in the aging microenvironment and age‐related diseases
Yin, Y., Chen, H., Wang, Y., Zhang, L., & Wang, X. (2021) · Journal of Extracellular Vesicles · doi:10.1002/jev2.12154 · Cited by 205
Oncogene-induced senescence: a double edged sword in cancer
Liu, X., Ding, J., & Meng, L. (2018) · Acta Pharmacologica Sinica · doi:10.1038/aps.2017.198 · Cited by 204
The Signaling of Cellular Senescence in Diabetic Nephropathy
Xiong, Y., & Zhou, L. (2019) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2019/7495629 · Cited by 185
“In histones, BRD4 binds to acetylated lysines, which results in the opening of chromatin and the activation of SASP process [217].”
BackgroundLiu, P., Li, F., Lin, J., Fukumoto, T., Nacarelli, T., Hao, X., Kossenkov, A. V., Simon, M. C., & Zhang, R. (2021) · Nature Cell Biology · doi:10.1038/s41556-021-00656-3 · Cited by 185
Senescence as a therapeutic target in cancer and age-related diseases
McHugh, D., Durán, I., & Gil, J. (2025) · Nature Reviews Drug Discovery · doi:10.1038/s41573-024-01074-4 · Cited by 197
“SASP expression is regulated by the mTOR pathway and involves the activation of multiple pathways including DDR 151 or p38 MAPK 152 , eventually engaging a programme involving super-enhancer remodelling 153 and activation of transcription factors such as NF-κB or C/EBPβ 154,155 .”
Senescence in Wound Repair: Emerging Strategies to Target Chronic Healing Wounds
Wilkinson, H. N., & Hardman, M. J. (2020) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2020.00773 · Cited by 173
Spatial and Temporal Control of Senescence
Ito, Y., Hoare, M., & Narita, M. (2017) · Trends in Cell Biology · doi:10.1016/j.tcb.2017.07.004 · Cited by 178
Targeting Cancer Cells with BET Bromodomain InhibitorsPreprint
Xu, Y., & Vakoc, C. R. (2017) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a026674 · Cited by 187
“The latter phenotype may reflect the emerging role for BRD4 in tumor suppression, and hence BET inhibition might be expected to worsen certain malignancies (Alsarraj and Hunter 2012; Fernandez et al. 2014; Tasdemir et al. 2016).”
BackgroundSelf-citationCellular senescence and the tumour microenvironment
Takasugi, M., Yoshida, Y., & Ohtani, N. (2022) · Molecular Oncology · doi:10.1002/1878-0261.13268 · Cited by 190
Cellular Senescence: From Mechanisms to Current Biomarkers and Senotherapies
Lucas, V., Cavadas, C., & Aveleira, C. A. (2023) · Pharmacological Reviews · doi:10.1124/pharmrev.122.000622 · Cited by 172
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
“0001 (Figure S4C-D and TS7) based on stringent criteria reported previously(Tasdemir et al., 2016).”
BackgroundResultInfluentialThe Senescence-Associated Secretory Phenotype: Critical Effector in Skin Cancer and Aging
Ghosh, K., & Capell, B. C. (2016) · Journal of Investigative Dermatology · doi:10.1016/j.jid.2016.06.621 · Cited by 171
“A uthor M anuscript A uthor M anuscript A uthor M anuscript A uthor M anuscript epigenetic activity, inhibition of Brd4 with small molecule BET inhibitors could prevent the SASP in these studies (Tasdemir et al., 2016).”
BackgroundMuñoz, D. P., Yannone, S. M., Daemen, A., Sun, Y., Vakar-Lopez, F., Kawahara, M., Freund, A. M., Rodier, F., Wu, J. D., Desprez, P.-Y., et al. (2019) · JCI Insight · doi:10.1172/jci.insight.124716 · Cited by 162
“So, therapeutic manipulations dampening the SASP, such as inhibitors of BET motifs (9), NF-κB (78), mTOR (79), or cGAS/STING signaling (80), may mitigate the detrimental effects of residual SnCs and restore tumor immunosurveillance.”
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
COVID-19 and cellular senescence
Schmitt, C. A., Tchkonia, T., Niedernhofer, L. J., Robbins, P. D., Kirkland, J. L., & Lee, S. (2023) · Nature Reviews Immunology · doi:10.1038/s41577-022-00785-2 · Cited by 153
Watt, A. C. S., & Goel, S. (2022) · Breast Cancer Research · doi:10.1186/s13058-022-01510-6 · Cited by 155
Single-cell senescence identification reveals senescence heterogeneity, trajectory, and modulators
Tao, W., Yu, Z., & Han, J.-D. J. (2024) · Cell Metabolism · doi:10.1016/j.cmet.2024.03.009 · Cited by 147
Kaempferol: Paving the path for advanced treatments in aging-related diseases
Hussain, M. S., Altamimi, A. S. A., Afzal, M., Almalki, W. H., Kazmi, I. A., Alzarea, S. I., Gupta, G., Shahwan, M. J., Kukreti, N., Wong, L. S., et al. (2024) · Experimental Gerontology · doi:10.1016/j.exger.2024.112389 · Cited by 146
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“BRD4, a member of Bromodomain and extraterminal domain (BET) proteins, plays pivotal roles in inflammation through assembly of acetylated histone and acetylation-dependent chromatin complexes on inflammatory genes [20, 21].”
BackgroundSenescence and the tumor-immune landscape: Implications for cancer immunotherapy
Chibaya, L., Snyder, J. T., & Ruscetti, M. A. (2022) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2022.02.005 · Cited by 146
INX-315, a Selective CDK2 Inhibitor, Induces Cell Cycle Arrest and Senescence in Solid Tumors
Dietrich, C. A., Trub, A. G., Ahn, A., Taylor, M., Ambani, K., Chan, K. T., Lu, K., Mahendra, C. A., Blyth, C., Coulson, R. S., et al. (2023) · Cancer Discovery · doi:10.1158/2159-8290.cd-23-0954 · Cited by 142
“Given the critical role of chromatin remodeling in governing the senescence phenotype (29, 30, 37), we performed the Assay for Transposase-Accessible Chromatin with Sequencing (ATAC-seq) on (i) parental cells treated with control vehicle or abemaciclib; (ii) abemaciclib-and abemaciclib/…”
The Chromatin Landscape of Cellular Senescence
Criscione, S. W., Teo, Y. V., & Neretti, N. (2016) · Trends in Genetics · doi:10.1016/j.tig.2016.09.005 · Cited by 137
“For example, it was recently reported that in OIS, the enhancer landscape undergoes global remodeling, with recruitment of BRD4 to newly activated super-enhancers proximal to SASP genes [91].”
BackgroundCancer and Aging - the Inflammatory Connection
Zinger, A., Cho, W. C. S., & Ben‐Yehuda, A. (2017) · Aging and Disease · doi:10.14336/ad.2016.1230 · Cited by 138
“ChIP-seq analysis showed that BRD4 is recruited to the new SE and participate in regulation of critical SASP genes [72].”
MethodLi, D., Wang, J., Zhang, M., Hu, X., She, J., Qiu, X., Zhang, X., Xu, L., Liu, Y., & Qin, S. (2019) · Molecular Therapy — Nucleic Acids · doi:10.1016/j.omtn.2019.11.003 · Cited by 138
“Mountains of evidence showed that histone modifications were one of the manners to regulate gene expression.22 Among diverse kinds of the histone modifications, H3K27ac mark was especially recognized by the BET family of bromodomain proteins, such as BRD4.”
BackgroundSARS-CoV-2 Mediated Endothelial Dysfunction: The Potential Role of Chronic Oxidative Stress
Chang, R. P., Mamun, A., Dominic, A., & Le, N. (2021) · Frontiers in Physiology · doi:10.3389/fphys.2020.605908 · Cited by 136
Putting the brakes on the cell cycle: mechanisms of cellular growth arrest
Pack, L. R., Daigh, L. H., & Meyer, T. (2019) · Current Opinion in Cell Biology · doi:10.1016/j.ceb.2019.05.005 · Cited by 139
“Alterations in chromatin dynamics may contribute to increased transcription of inflammatory cytokines in senescent cells [67,68].”
BackgroundEpigenetic Regulation of Cellular Senescence
Crouch, J. D., Shvedova, M., Thanapaul, R. J. R. S., Botchkarev, V. A., & Roh, D. S. (2022) · Cells · doi:10.3390/cells11040672 · Cited by 139
“Further, pharmacological inhibition of BRD4 allowed for immune escape and decreased clearance of premalignant senescent hepatocytes in a liver cancer mouse model [121].”
BackgroundInfluentialTargeting Senescent Cells for a Healthier Aging: Challenges and Opportunities
Song, S., Tchkonia, T., Jiang, J., Kirkland, J. L., & Sun, Y. (2020) · Advanced Science · doi:10.1002/advs.202002611 · Cited by 129
YY1 complex in M2 macrophage promotes prostate cancer progression by upregulating IL-6
Chen, S., Lǚ, K., Hou, Y., You, Z., Shu, C., Wei, X., Wu, T., Shi, N., Zhang, G., Wu, J., et al. (2023) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2022-006020 · Cited by 132
Chibaya, L., Murphy, K. C., DeMarco, K. D., Gopalan, S., Liu, H., Parikh, C. N., Lopez-Diaz, Y., Faulkner, M., Li, J., Morris, J. P., et al. (2023) · Nature Cancer · doi:10.1038/s43018-023-00553-8 · Cited by 138
Self-citationEmerging roles of and therapeutic strategies targeting BRD4 in cancer
White, M. E., Fenger, J. M., & Carson, W. E. (2019) · Cellular Immunology · doi:10.1016/j.cellimm.2019.02.001 · Cited by 124
“Senescent cells normally maintain a closed chromatin configuration; however, cancer cells can acquire a secretory-associated senescent phenotype (SASP) whereby oncogene-induced senescence results in remodeling of the enhancer landscape and recruitment of BRD4 [21].”
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“, 2015); BRD4 functions as an epigenetic reader to modulate lineage- and cellular state-specific transcription (Tasdemir et al., 2016); finally, cGAS-STING is a component of the innate immune system that senses the presence of cytosolic DNA (Yang et al.”
BackgroundInfluentialCellular senescence in lung cancer: Molecular mechanisms and therapeutic interventions
Jha, S. K., Rubis, G. D., Devkota, S. R., Zhang, Y., Adhikari, R., Jha, L. A., Bhattacharya, K., Mehndiratta, S., Gupta, G., Singh, S. K., et al. (2024) · Ageing Research Reviews · doi:10.1016/j.arr.2024.102315 · Cited by 138
“When HRAS G12V -induced senescent human cultured fibroblasts were injected into mice, it was observed that the super-enhancer landscape in these cells underwent global remodeling (Regis et al., 2009; Tasdemir et al., 2016) .”
Bromodomain 4: a cellular Swiss army knife
Devaiah, B. N., Gégonne, A., & Singer, D. S. (2016) · Journal of Leukocyte Biology · doi:10.1189/jlb.2ri0616-250r · Cited by 124
“senescence, although it is not clear what determines which will occur [47] (unpublished observations).”
BackgroundCellular senescence: Neither irreversible nor reversible
Reimann, M., Lee, S., & Schmitt, C. A. (2024) · The Journal of Experimental Medicine · doi:10.1084/jem.20232136 · Cited by 125
A common signature of cellular senescence; does it exist?
Sikora, E., Bielak-Żmijewska, A., & Mosieniak, G. (2021) · Ageing Research Reviews · doi:10.1016/j.arr.2021.101458 · Cited by 124
The Paradoxical Role of Cellular Senescence in Cancer
Yang, J., Liu, M., Hong, D., Zeng, M., & Zhang, X. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.722205 · Cited by 125
“Furthermore, IL-6 may cooperate with HER2 in the process of tumor development (Korkaya et al., 2012; Tivari et al., 2018).”
BackgroundThe role of epigenetics in renal ageing
Shiels, P. G., McGuinness, D., Eriksson, M., Kooman, J. P., & Stenvinkel, P. (2017) · Nature Reviews Nephrology · doi:10.1038/nrneph.2017.78 · Cited by 114
Oncogene-induced senescence: From biology to therapy
Zhu, H., Blake, S., Kusuma, F. K., Pearson, R. B., Kang, J., & Chan, K. T. (2020) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2020.111229 · Cited by 116
The Functions of BET Proteins in Gene Transcription of Biology and Diseases
Cheung, K. L., Kim, C., & Zhou, M. (2021) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2021.728777 · Cited by 115
“…studies to identify key genes and reveal mechanisms of BET proteins in disease-related cell types and genes such as rheumatoid arthritis synovial fibroblasts (Krishna et al., 2021), ESC pluripotency genes (Di Micco et al., 2014), and senescence-associated secretory genes (Tasdemir et al., 2016).”
BackgroundWatt, A. C. S., Cejas, P., DeCristo, M. J., Metzger, O., Lam, E. Y. N., Qiu, X., BrinJones, H., Kesten, N., Coulson, R. S., Font‐Tello, A., et al. (2020) · Nature Cancer · doi:10.1038/s43018-020-00135-y · Cited by 112
Targeting senescent cells for a healthier longevity: the roadmap for an era of global aging
Sun, Y., Li, Q., & Kirkland, J. L. (2022) · Life Medicine · doi:10.1093/lifemedi/lnac030 · Cited by 105
Senescent cells and macrophages: key players for regeneration?
Elder, S. S., & Emmerson, E. (2020) · Open Biology · doi:10.1098/rsob.200309 · Cited by 114
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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