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Super-Enhancers in the Control of Cell Identity and Disease
Open accessAbstract
Super-enhancers are large clusters of transcriptional enhancers that drive expression of genes that define cell identity. Improved understanding of the roles that super-enhancers play in biology would be afforded by knowing the constellation of factors that constitute these domains and by identifying super-enhancers across the spectrum of human cell types. We describe here the population of transcription factors, cofactors, chromatin regulators, and transcription apparatus occupying super-enhancers in embryonic stem cells and evidence that super-enhancers are highly transcribed. We produce a catalog of super-enhancers in a broad range of human cell types and find that super-enhancers associate with genes that control and define the biology of these cells. Interestingly, disease-associated variation is especially enriched in the super-enhancers of disease-relevant cell types. Furthermore, we find that cancer cells generate super-enhancers at oncogenes and other genes important in tumor pathogenesis. Thus, super-enhancers play key roles in human cell identity in health and in disease.
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“In mammals, cellular identity is established prenatally and maintained by H3K27ac-enriched super-enhancers (Hnisz et al., 2013; Whyte et al., 2013).”
From Loss of epigenetic information as a cause of mammalian aging (2023) · cites this paper as Hnisz et al., 2013
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“The level of the active enhancer chromatin mark, H3K27ac, is not skewed in a similar manner towards these two locations, indicating that these regions are not super-enhancers”
From The transcriptional cofactor TRIM33 prevents apoptosis in B lymphoblastic leukemia by deactivating a single enhancer (2015) · cites this paper as Hnisz et al., 2013
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“Super-enhancers commonly drive high-level expression of tissue-specific genes, including miRNA genes, with evolutionarily conserved cell type-specific function11–13.”
From Gain-of-function mutation of microRNA-140 in human skeletal dysplasia (2019) · cites this paper as [13]
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“SEs in both HCC and TAN were associated with GO terms related to metabolic genes (e.g. CYP3A4, SLC38A4, and IGFBP1) (Fig. 2c)20,21,58.”
From Multi-omic analysis of hepatocellular carcinoma reveals aberrant cis-regulatory changes and dysregulated retrotransposons with prognostic potential (2025) · cites this paper as [20]
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In the citing paper
“Clusters of multiple enhancers, referred to as super enhancers, are particularly important in driving the expression of cell identity genes (6).”
From Brain cell type–specific enhancer–promoter interactome maps and disease - risk association (2019) · cites this paper as [6]
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“Many Hep‐IDCONNECT TFs, including NR1H3 and THRB, do not display typically used features to define hepatocyte identity TFs such as hepatocyte‐specific expression and association with super‐enhancers (Hnisz et al, 2013; Dubois et al, 2020a; Table EV3).”
From An extended transcription factor regulatory network controls hepatocyte identity (2023) · cites this paper as Hnisz et al, 2013
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“Some enhancers reside in clusters of a handful116 to even hundreds (‘super enhancers’76,117), whereas many are solo.”
From Towards a comprehensive catalogue of validated and target-linked human enhancers (2020) · cites this paper as [117]
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“we detected binding of liver-restricted TFs (C/EBPα/β, HNF1A, and HNF4A), pioneering TFs (CEBPα/β, FOXA2, and FOXA3), and Wnt-signaling TFs (TCF7) at individual constituent enhancers (Fig. 3b)20,21.”
From Multi-omic analysis of hepatocellular carcinoma reveals aberrant cis-regulatory changes and dysregulated retrotransposons with prognostic potential (2025) · cites this paper as [20]
Experimental — accuracy not yet measuredIn the citing paper
“suggesting that H3K27M participates in the formation of super enhancer-like elements purported to play a key role in cancer14.”
From Therapeutic targeting of polycomb and BET bromodomain proteins in diffuse intrinsic pontine gliomas (2017) · cites this paper as [14]
In the citing paper
“This mystery, which we will call the enhancer-gene specificity conundrum, is important to solve because the majority of disease-associated non-coding variation occurs in the vicinity of enhancers and thus likely impacts these enhancers’ target genes (Ernst et al., 2011; Farh et al., 2015; Hnisz et al., 2013; Maurano et al., 2012).”
From Insulated Neighborhoods: Structural and Functional Units of Mammalian Gene Control (2016) · cites this paper as Hnisz et al., 2013
In the citing paper
“Tens of thousands of non-coding genetic variants have been linked with various human diseases and traits in genome-wide association studies (GWAS), and the majority of these variants occur in enhancers (Ernst et al., 2011; Farh et al., 2015; Hnisz et al., 2013; Maurano et al., 2012).”
From Insulated Neighborhoods: Structural and Functional Units of Mammalian Gene Control (2016) · cites this paper as Hnisz et al., 2013
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“Compounding this issue is the recognition of the asymmetric organization of enhancers and extensive modification of selected genomic regions, engaging large amounts of TFs to multiple neighboring enhancer sites that assemble as so called super- or stretch-enhancers (Hnisz et al., 2013; Lovén et al., 2013; Whyte et al.…”
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“These results are in keeping with the notion that SEs are more active than TEs (2,3).”
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“For example, recent studies have demonstrated evidence for super-enhancers, which function in long-range regulation and are associated with an enrichment of activating histone marks [41,42].”
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“Generally, SEs were thought to promote tumorigenesis and malignancy, based on the reports that SEs upregulate oncogenes whereas broad H3K4me3 peaked at tumor suppressor genes (Hnisz et al., 2013; Chen et al., 2015).”
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Molecular Mechanisms of MYCN Dysregulation in Cancers
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The era of gene therapy: From preclinical development to clinical application
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Zheng, Z., Xia, L., Hu, G.-S., Liu, J., Hu, Y.-H., Chen, Y.-J., Jia-yin, P., Zhang, W., & Liu, W. (2022) · Nucleic Acids Research · doi:10.1093/nar/gkac778 · Cited by 62
“Super-enhancers (SEs) are large clusters of enhancers that drive the expression of genes with implications in cell identity and diseases (5,6).”
BackgroundVarberg, K. M., Dominguez, E. M., Koseva, B. S., Varberg, J. M., McNally, R. P., Moreno‐Irusta, A., Wesley, E. R., Iqbal, K., Cheung, W., Schwendinger-Schreck, C., et al. (2023) · Nature Communications · doi:10.1038/s41467-023-40424-5 · Cited by 67
“To test this, we used the ATAC-Seq data to identify super-enhancers based on established algorithms 34 .”
Targeting lysine acetylation readers and writers
Zhou, M., & Cole, P. A. (2024) · Nature Reviews Drug Discovery · doi:10.1038/s41573-024-01080-6 · Cited by 68
“BET proteins facilitate chromatin opening, recruit transcription factors and coactivators to gene promoters and enhancers 76 , and release paused RNA polymerase II complexes to promote active gene transcription 77 .”
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“Four representative samples of these ATC-specific SEs are shown in Figure 5C.”
InfluentialShang, S., Yang, J., Jazaeri, A. A., Duval, A. J., Tufan, T., Fischer, N. L., Benamar, M., Guessous, F., Lee, I.-Y., Campbell, R. M., et al. (2019) · Cancer Research · doi:10.1158/0008-5472.can-19-0215 · Cited by 67
“Given the known role of SEs in driving the expression of key cell type-specific master regulators, we further prioritized the list of TFs by focusing on resistant-specific SE-regulated TFs. Notably, among the significantly upregulated and SE-associated TFs were multiple previously known players of chemoresistance incl…”
BackgroundInfluentialChen, H., Du, G., Song, X., & Li, L. (2017) · Genomics, Proteomics & Bioinformatics · doi:10.1016/j.gpb.2017.02.003 · Cited by 85
Corradin, O., Cohen, A. J., Luppino, J. M., Bayles, I., Schumacher, F. R., & Scacheri, P. C. (2016) · Nature Genetics · doi:10.1038/ng.3674 · Cited by 63
General mechanism of JQ1 in inhibiting various types of cancer
Jiang, G., Deng, W., Liu, Y., & Wang, C. (2020) · Molecular Medicine Reports · doi:10.3892/mmr.2020.10927 · Cited by 62
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Core transcription regulatory circuitry orchestrates corneal epithelial homeostasis
Li, M., Huang, H., Li, L., He, C., Zhu, L., Guo, H., Wang, L., Liu, J., Wu, S., Liu, J., et al. (2021) · Nature Communications · doi:10.1038/s41467-020-20713-z · Cited by 61
Emerging Principles in the Transcriptional Control by YAP and TAZ
Lopez-Hernandez, A., Sberna, S., & Campaner, S. (2021) · Cancers · doi:10.3390/cancers13164242 · Cited by 60
BRD4-targeting PROTAC as a unique tool to study biomolecular condensates
Shi, Y., Liao, Y., Liu, Q., Ni, Z., Zhang, Z., Shi, M., Li, P., Li, H., & Rao, Y. (2023) · Cell Discovery · doi:10.1038/s41421-023-00544-0 · Cited by 66
Čekan, P., Hasegawa, K., Pan, Y., Tubman, E. S., Odde, D. J., Chen, J.-Q., Herrmann, M. A., Kumar, S., & Kaláb, P. (2016) · Molecular Biology of the Cell · doi:10.1091/mbc.e16-01-0025 · Cited by 62
“6 HCT116 cells (Hnisz et al., 2013), which is a well-studied model of resistance to DNA damage-inducing chemotherapy (Chang et al.”
BackgroundGarcía-Carpizo, V., Sarmentero, J., Han, B., Graña‐Castro, O., Ruiz‐Llorente, S., Pisano, D. G., Serrano, M., Brooks, H. B., Campbell, R. M., & Barrero, M. J. (2016) · Scientific Reports · doi:10.1038/srep32952 · Cited by 62
Molecular pathology of paediatric central nervous system tumours
Chiang, J., & Ellison, D. W. (2016) · The Journal of Pathology · doi:10.1002/path.4813 · Cited by 63
“Structural alterations that aberrantly induce the proto-oncogenes GFI1 or GF1B through highly active enhancer elements (enhancer hijacking) [121] occur in 41% of group 3 and 10% of group 4 tumours [122].”
BackgroundTAL1 as a master oncogenic transcription factor in T-cell acute lymphoblastic leukemia
Sanda, T., & Leong, W. Z. (2017) · Experimental Hematology · doi:10.1016/j.exphem.2017.06.001 · Cited by 62
Kycia, I., Wolford, B. N., Huyghe, J. R., Fuchsberger, C., Vadlamudi, S., Kursawe, R., Welch, R., Albanus, R. D., Uyar, A., Khetan, S., et al. (2018) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2018.02.020 · Cited by 58
“rs7163757 Resides in an Islet SE Constituent Open Chromatin Site SEs can encompass multiple, discrete open chromatin sites.(16,17,53) We profiled chromatin accessibility in human islets by using ATAC-seq(31) to determine the constituent open chromatin sites within the C2CD4A-C2CD4BVPS13C islet SE and to identify any o…”
MethodKubota, S., Tokunaga, K., Umezu, T., Yokomizo-Nakano, T., Sun, Y., Oshima, M., Tan, K., Yang, H., Kanai, A., Iwanaga, E., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-09710-z · Cited by 54
Wiese, M., Hamdan, F. H., Kubiak, K., Diederichs, C., Gielen, G. H., Nussbaumer, G., Carcaboso, A. M., Hulleman, E., Johnsen, S. A., & Kramm, C. M. (2020) · Cell Death and Disease · doi:10.1038/s41419-020-02800-7 · Cited by 60
Plasticity in Neuroblastoma Cell Identity Defines a Noradrenergic-to-Mesenchymal Transition (NMT)
Gautier, M., Thirant, C., Delattre, O., & Janoueix‐Lerosey, I. (2021) · Cancers · doi:10.3390/cancers13122904 · Cited by 60
“CRCs are TF networks with feed-forward auto-regulatory loops that establish cell fate decisions and maintain cell identity [26].”
BackgroundCofactor squelching: Artifact or fact?
Schmidt, S. F., Larsen, B. D., Loft, A., & Mandrup, S. (2016) · BioEssays · doi:10.1002/bies.201600034 · Cited by 56
“In line with the highly cell typespecific expression pattern of superenhancer-associated genes [40, 42], we also found that TNF represses highly cell type-selective gene programs across five different cell types, compared with a much more conserved activated inflammatory gene program [51].”
BackgroundDave, K., Sur, I., Yan, J., Zhang, J., Kaasinen, E., Zhong, F., Blaas, L., Li, X., Kharazi, S., Gustafsson, C., et al. (2017) · eLife · doi:10.7554/elife.23382 · Cited by 61
“This finding is consistent with the published data that regulatory elements controlling T-cell development and T-cell acute lymphoblastic leukemia are located 1.47 Mb downstream of the Myc ORF (Herranz et al., 2014).”
BackgroundInfluentialBojcsuk, D., Nagy, G., & Bálint, B. L. (2016) · Nucleic Acids Research · doi:10.1093/nar/gkw1283 · Cited by 63
“In cancer cells, SEs are associated with key oncogenes, such as c-MYC (16,18) and TAL1 (19); therefore, the genome-wide determination of SE-associated genes would be useful for mapping additional determinative genes that may be involved in tumor pathogenesis (20).”
BackgroundTargeting bromodomain and extraterminal proteins in breast cancer
Sahni, J. M., & Keri, R. A. (2017) · Pharmacological Research · doi:10.1016/j.phrs.2017.11.015 · Cited by 61
“SEs ary by cell type and the different binding sites in distinct cells nderlie the expression of cell identity genes that specify that cell ype [81,82].”
BackgroundBRCA1-associated R-loop affects transcription and differentiation in breast luminal epithelial cells
Chiang, H.-C., Zhang, X., Li, J., Zhao, X., Chen, J., Wang, H. T.-H., Jatoi, I., Brenner, A. J., Hu, Y., & Li, R. (2019) · Nucleic Acids Research · doi:10.1093/nar/gkz262 · Cited by 60
“By mining publicly available genomic databases, we found that the BRCA1 -associated R-loop resides within previously identified cis-regulatory elements for ESR1 (37,38), including a super-enhancer in MCF7 cells (39,40) (Figure 1A).”
A model of active transcription hubs that unifies the roles of active promoters and enhancers
Zhu, I., Song, W., Ovcharenko, I., & Landsman, D. (2021) · Nucleic Acids Research · doi:10.1093/nar/gkab235 · Cited by 55
“(16) showed plots of single signals like Med1 on enhancers with a similar shape to Figure 1B.”
BackgroundSuper-enhancers in transcriptional regulation and genome organization
Wang, X., Cairns, M. J., & Yan, J. (2019) · Nucleic Acids Research · doi:10.1093/nar/gkz1038 · Cited by 154
Dynamic enhancers control skeletal muscle identity and reprogramming
Ramachandran, K., Senagolage, M. D., Sommars, M. A., Futtner, C. R., Omura, Y., Allred, A. L., & Barish, G. D. (2019) · PLoS Biology · doi:10.1371/journal.pbio.3000467 · Cited by 61
“Analysis of H3K27ac or ATAC-seq identified several hundreds of SEs in muscles, whereas MED1 data yielded more limited numbers in each group, consistent with findings in other cells or tissues [23,24].”
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Zhu, Y., Yu, J., Gu, J., Xue, C., Zhang, L., Chen, J., & Shen, L. (2021) · Nucleic Acids Research · doi:10.1093/nar/gkab1069 · Cited by 59
The Yin and Yang of Chromatin Dynamics In Stem Cell Fate Selection
Adam, R. C., & Fuchs, E. V. (2015) · Trends in Genetics · doi:10.1016/j.tig.2015.11.002 · Cited by 62
“Recent evidence suggests that genes specifying cell identity and function are associated with densely spaced clusters of active enhancers referred to as ‘super-enhancers’, which recruit much of the cell's transcriptional apparatus (Box 2) [78-80].”
Epigenomic Landscape of Human Fetal Brain, Heart, and Liver
Yan, L., Guo, H., Hu, B., Li, R., Yong, J., Zhao, Y., Zhi, X., Fan, X., Guo, F., Wang, X., et al. (2015) · Journal of Biological Chemistry · doi:10.1074/jbc.m115.672931 · Cited by 59
“Analyses of Super-enhancers in Early Human Embryos— Recently, the super-enhancer has been identified to play a crucial role in cell fate determination during both embryonic development and tumor formation (44, 45, 47).”
BackgroundMethodHong, S. H., Eun, J. W., Choi, S. K., Shen, Q., Choi, W. S., Han, J., Nam, S. W., & You, J. S. (2016) · Oncotarget · doi:10.18632/oncotarget.8701 · Cited by 60
“[15, 19, 25, 26] We examined whether anti-tumorigenic effect of JQ1 is through MYC, firstly we checked MYC expression after treatment of JQ1 in SK-Hep1, Huh7 and HepG2 liver cancer cells.”
BackgroundGusev, A., Shi, H., Kichaev, G., Pomerantz, M., Li, F., Long, H. W., Ingles, S. A., Kittles, R. A., Strom, S. S., Rybicki, B. A., et al. (2016) · Nature Communications · doi:10.1038/ncomms10979 · Cited by 51
Distinctions between transgenerational and non-transgenerational epimutations
McCarrey, J. R. (2014) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2014.07.016 · Cited by 58
lncRNAs and MYC: An Intricate Relationship
Iaccarino, I. (2017) · International Journal of Molecular Sciences · doi:10.3390/ijms18071497 · Cited by 60
“Interestingly, looking at the ChromHMM Segmentations analysis from the ENCODE Project [68] and at the RNA-seq data from the same cell lines, it is possible to notice that the CCAT1 locus can have very different activities according to the cell of origin: in the lymphoblastoid cell line GM12878 the locus has marks of a…”
BackgroundMethodEnhancer dependence of cell-type–specific gene expression increases with developmental age
Cai, W., Huang, J., Zhu, Q., Li, B. E., Seruggia, D., Zhou, P., Nguyen, M., Fujiwara, Y., Xie, H., Yang, Z., et al. (2020) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2008672117 · Cited by 56
“diseases, as the vast majority of disease-associated variations occur within noncoding genomic sequences (2, 33).”
BackgroundThe genome-wide impact of trisomy 21 on DNA methylation and its implications for hematopoiesis
Muskens, I. S., Li, S., Jackson, T., Elliott, N., Hansen, H. M., Myint, S. S., Pandey, P., Schraw, J. M., Roy, R., Anguiano, J., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-21064-z · Cited by 62
Jarroux, J., Foretek, D., Bertrand, C., Gabriel, M., Szachnowski, U., Saci, Z., Guo, S., Londoño‐Vallejo, A., Pinskaya, M., & Morillon, A. (2021) · EMBO Reports · doi:10.15252/embr.202050193 · Cited by 63
“This histone modification is present at promoters of transcribed genes, reflecting transcriptional activity of the locus, but also it is a hallmark of active enhancers and super-enhancers in the genome (Creyghton et al, 2010; Hnisz et al, 2013).”
The interplay of mutagenesis and ecDNA shapes urothelial cancer evolution
Nguyen, D., Hooper, W. F., Liu, W., Chu, T. R., Geiger, H. M., Shelton, J. M., Shah, M. J., Goldstein, Z. R., Winterkorn, L. H., Helland, A., et al. (2024) · Nature · doi:10.1038/s41586-024-07955-3 · Cited by 62
Anandhakumar, J., Moustafa, Y. W., Chowdhary, S., Kainth, A. S., & Gross, D. S. (2016) · Molecular and Cellular Biology · doi:10.1128/mcb.00005-16 · Cited by 58
“Additionally, disease states such as cancer, diabetes, and neurodegeneration can arise from misregulated gene transcription (3).”
BackgroundPlatelet function is modified by common sequence variation in megakaryocyte super enhancers
Petersen, R., Lambourne, J. J., Javierre, B. M., Grassi, L., Kreuzhuber, R., Ruklisa, D., Rosa, I. M., Tomé, A. R., Elding, H., van Geffen, J. P., et al. (2017) · Nature Communications · doi:10.1038/ncomms16058 · Cited by 56
Eliades, P. J., Abraham, B. J., Ji, Z., Miller, D. M., Christensen, C. L., Kwiatkowski, N. P., Kumar, R., Njauw, C.-N. J., Taylor, M., Miao, B., et al. (2018) · Journal of Investigative Dermatology · doi:10.1016/j.jid.2017.09.056 · Cited by 60
“SEs are also acquired by tumor cells at key oncogenes, are capable of energizing gene expression, and, importantly, are exquisitely sensitive to transcriptional disruption (Hnisz et al., 2013; Loven et al., 2013; Whyte et al., 2013).”
BackgroundSelf-citationCREBBP/EP300 bromodomains are critical to sustain the GATA1/MYC regulatory axis in proliferation
García-Carpizo, V., Ruiz‐Llorente, S., Sarmentero, J., Graña‐Castro, O., Pisano, D. G., & Barrero, M. J. (2018) · Epigenetics & Chromatin · doi:10.1186/s13072-018-0197-x · Cited by 58
“First, CREBBP and EP300 are highly enriched at superenhancers compared to regular enhancers [8] and second, EP300 is recruited by hematopoietic transcription factors to mediate histone acetylation at critical regulatory regions and support BRD4 occupancy in mouse leukemia cells 2 [9].”
BackgroundResultBempt, M. V., Demeyer, S., Broux, M., Bie, J. D., Bornschein, S., Mentens, N., Vandepoel, R., Geerdens, E., Radaelli, E., Bornhauser, B. C., et al. (2018) · Cancer Cell · doi:10.1016/j.ccell.2018.07.007 · Cited by 58
Metadata
- Authors
- Hnisz, D., Abraham, B. J., Lee, T. I., Lau, A., Saint-André, V., Sigova, A. A., Hoke, H. A., & Young, R. A.
- Affiliations
- Whitehead Institute for Biomedical Research (US)
- Corresponding author
- Young, Richard A.
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2013-11
- Volume
- 155
- Issue
- 4
- Pages
- 934-947
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC3841062
- OpenAlex
- W2004966039
- Cited by
- 3,662
- References
- 164
- Citations by year
- 2026: 182 · 2025: 294 · 2024: 332 · 2023: 321 · 2022: 360 · 2021: 406 · 2020: 331 · 2019: 315 · 2018: 291 · 2017: 259 · 2016: 232 · 2015: 215 · 2014: 110 · 2013: 5
- FWCI
- 83.97
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- HAL (submittedVersion)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc-nd)
- PMC
- Funders
- University of California
- National Institutes of Health (CA146445, HG002668, CA109901, P30AG10161, R01AG36042, R01AG17917, RC2AG36547)
- Topics
- 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
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Keywords
- super-enhancers, enhancers, cell identity, transcription factors, chromatin regulators, embryonic stem cells, oncogenes, cancer, enhancer transcription, human cell types
- MeSH terms
- Animals, Chromatin, Enhancer Elements, Genetic, Humans, Neoplasms, RNA Polymerase II, Transcription Factors, Transcription, Genetic, Polymorphism, Single Nucleotide, Embryonic Stem Cells
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