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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
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.
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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]
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
“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]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
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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In the citing paper
“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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In the citing paper
“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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The transcription factor Bcl11b promotes both canonical and adaptive NK cell differentiation
Holmes, T. D., Pandey, R. V., Helm, E. Y., Schlums, H., Han, H., Campbell, T. M., Drashansky, T. T., Chiang, S. C. C., Wu, C.-Y., Tao, C., et al. (2021) · Science Immunology · doi:10.1126/sciimmunol.abc9801 · Cited by 100
Understanding Celiac Disease by Genomics
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Engelen, E., Brandsma, J. H., Moen, M. J., Signorile, L., Dekkers, D. H. W., Demmers, J., Kockx, C. E. M., Özgür, Z., van IJcken, W. F. J., van den Berg, D. L. C., et al. (2015) · Nature Communications · doi:10.1038/ncomms8155 · Cited by 98
Unravelling the genomic targets of small molecules using high-throughput sequencing
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Chromatin features and the epigenetic regulation of pluripotency states in ESCs
Tee, W., & Reinberg, D. (2014) · Development · doi:10.1242/dev.096982 · Cited by 98
Jin, Y., Chen, K., Paepe, A. D., Hellqvist, E., Krstic, A. D., Metang, L. A., Gustafsson, C., Davis, R. E., Levy, Y. M., Surapaneni, R., et al. (2018) · Blood · doi:10.1182/blood-2017-09-808063 · Cited by 96
Meng, F., Zhao, H., Zhu, B., Zhang, T., Yang, M., Li, Y., Han, Y., & Jiang, J. (2021) · The Plant Cell · doi:10.1093/plcell/koab093 · Cited by 94
Xiong, F., Wang, R., Lee, J.-H., Li, S., Chen, S.-F., Liao, Z., Hasani, L. A., Nguyen, P. T.-M., Zhu, X., Krakowiak, J., et al. (2021) · Cell Research · doi:10.1038/s41422-021-00515-8 · Cited by 107
Lu, B., Zou, C., Yang, M., He, Y., He, J., Zhang, C., Chen, S., Yu, J., Liu, K. Y., Cao, Q., et al. (2021) · Advanced Science · doi:10.1002/advs.202101895 · Cited by 95
RANKL-responsive epigenetic mechanism reprograms macrophages into bone-resorbing osteoclasts
Bae, S., Kim, K., Kang, K., Kim, H., Lee, M. J., Oh, B., Kaneko, K., Ma, S., Choi, J., Kwak, H., et al. (2022) · Cellular and Molecular Immunology · doi:10.1038/s41423-022-00959-x · Cited by 104
“SEs have been previously shown to be closely associated with the expression of master transcription factors (TFs) that control cell identity and fate [24, 26].”
BackgroundFive endometrial cancer risk loci identified through genome-wide association analysis
National Study of Endometrial Cancer Genetics Group (NSECG), Cheng, T. H. T., Chenevix‐Trench, G., RENDOCAS, Chenevix‐Trench, G., Thompson, D. J., O’Mara, T. A., Painter, J. N., Glubb, D. M., Flach, S., et al. (2016) · Nature Genetics · doi:10.1038/ng.3562 · Cited by 94
A KLF6-driven transcriptional network links lipid homeostasis and tumour growth in renal carcinoma
Syafruddin, S. E., Rodrigues, P., Vojtasova, E., Patel, S. A., Zaini, M. N., Burge, J., Warren, A. Y., Stewart, G. D., Eisen, T. G., Bihary, D., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-09116-x · Cited by 97
Dense and accurate whole-chromosome haplotyping of individual genomes
Porubskỳ, D., Garg, S., Sanders, A. D., Korbel, J. O., Guryev, V., Lansdorp, P. M., & Marschall, T. (2017) · Nature Communications · doi:10.1038/s41467-017-01389-4 · Cited by 95
“This is critical as many variants that have been linked to traits in genome-wide association studies reside in (super) enhancers 6 and enhancer-speci fi c variants can show epistatic effects among one another 7 , as well as with their target genes that are beyond the reach of linkage disequilibrium…”
BackgroundTesting the super-enhancer concept
Blobel, G. A., Higgs, D. R., Mitchell, J. A., Notani, D., & Young, R. A. (2021) · Nature Reviews Genetics · doi:10.1038/s41576-021-00398-w · Cited by 98
Self-citationLenhart, R., Kirov, S. A., Desilva, H., Cao, J., Lei, M., Johnston, K., Peterson, R., Schweizer, L., Purandare, A. V., Ross‐Macdonald, P., et al. (2015) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-15-0037 · Cited by 95
Tex10 Coordinates Epigenetic Control of Super-Enhancer Activity in Pluripotency and Reprogramming
Ding, J., Huang, X., Shao, N., Zhou, H., Lee, D., Faiola, F., Fidalgo, M., Guallar, D., Saunders, A., Shliaha, P. V., et al. (2015) · Cell stem cell · doi:10.1016/j.stem.2015.04.001 · Cited by 93
“Active enhancers are also bound by general TFs and RNA polymerase II (Pol II), leading to the production of eRNAs in SEs, and to a lesser extent, in TEs (Hnisz et al., 2013).”
BackgroundMethodInfluentialLi, P., Mitra, S., Spolski, R. J., Oh, J., Liao, W., Tang, Z., Mo, F., Li, X., West, E. E., Gromer, D. J., et al. (2017) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1714019114 · Cited by 94
Sanchez, G. J., Richmond, P. A., Bunker, E. N., Karman, S. S., Azofeifa, J. G., Garnett, A. T., Xu, Q., Wheeler, G. E., Toomey, C. M., Zhang, Q., et al. (2017) · Nucleic Acids Research · doi:10.1093/nar/gkx1225 · Cited by 92
“Initially identified as large clusters of transcription factor binding sites (37,38), super-enhancers have been shown to be involved in driving expression of genes that play prominent roles in cell proliferation and differentiation (39).”
BackgroundUSP7 Cooperates with NOTCH1 to Drive the Oncogenic Transcriptional Program in T-Cell Leukemia
Jin, Q., Martinez, C. A., Arcipowski, K. M., Zhu, Y., Gutierrez-Diaz, B. T., Wang, K. K., Johnson, M. R., Volk, A. G., Wang, F., Wu, J., et al. (2018) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-18-1740 · Cited by 98
“In agreement with the association of SEs with transcriptional activation, we found that the USP7-bound genes were more highly expressed compared to the rest of the transcriptome (Fig.”
InfluentialPulikkan, J. A., Hegde, M. B., Ahmad, H. M., Belaghzal, H., Illendula, A., Yu, J., O’Hagan, K., Ou, J., Müller‐Tidow, C., Wolfe, S. A., et al. (2018) · Cell · doi:10.1016/j.cell.2018.05.048 · Cited by 92
Mijnheer, G., Lutter, L., Mokrý, M., van der Wal, M., Scholman, R. C., Fleskens, V., Pandit, A., Tao, W., Wekking, M., Vervoort, S. J., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-22975-7 · Cited by 96
Emerging concepts of epigenetic dysregulation in hematological malignancies
Ntziachristos, P., Abdel-Wahab, O. I., & Aifantis, I. (2016) · Nature Immunology · doi:10.1038/ni.3517 · Cited by 99
Abruzzese, M. P., Bilotta, M. T., Fionda, C., Zingoni, A., Soriani, A., Vulpis, E., Borrelli, C., Zitti, B., Petrucci, M. T., Ricciardi, M. R., et al. (2016) · Journal of Hematology & Oncology · doi:10.1186/s13045-016-0362-2 · Cited by 97
Small genomic insertions form enhancers that misregulate oncogenes
Abraham, B. J., Hnisz, D., Weintraub, A. S., Kwiatkowski, N. P., Li, C. H., Li, Z., Weichert‐Leahey, N., Rahman, S., Liu, Y., Etchin, J., et al. (2017) · Nature Communications · doi:10.1038/ncomms14385 · Cited by 96
Self-citationmiRNA-32 Drives Brown Fat Thermogenesis and Trans-activates Subcutaneous White Fat Browning in Mice
Ng, R., Hussain, N. A., Zhang, Q., Chang, C. T., Li, H., Fu, Y., Cao, L., Han, W., Stünkel, W., & Xu, F. (2017) · Cell Reports · doi:10.1016/j.celrep.2017.04.035 · Cited by 93
“Super-Enhancer Identification and Visualization Super-enhancers were identified using ROSE: rank ordering of super-enhancer from the Young Lab (Hnisz et al., 2013; Whyte et al., 2013).”
BackgroundMethodHogan, N. T., Whalen, M. B., Stolze, L. K., Hadeli, N. K., Lam, M. T. Y., Springstead, J. R., Glass, C. K., & Romanoski, C. E. (2017) · eLife · doi:10.7554/elife.22536 · Cited by 92
“To narrow the search in HAECs, we hypothesized that the operational TFs would be highly expressed and that their genetic loci would contain super-enhancers (SEs), or unusually dense clusters of highly decorated enhancers (Hnisz et al., 2013).”
BackgroundHigh OGT activity is essential for MYC-driven proliferation of prostate cancer cells
Itkonen, H. M., Urbanucci, A., Martin, S. E. S., Khan, A., Mathelier, A., Thiede, B., Walker, S., & Mills, I. G. (2019) · Theranostics · doi:10.7150/thno.30834 · Cited by 93
“Super-enhancers (SE) are cell-type specific enhancers of highly transcribed genes [46].”
BackgroundChen, L., Huang, M., Plummer, J., Pan, J., Jiang, Y. Y., Yang, Q., Silva, T. C., Gull, N., Chen, S., Ding, L., et al. (2019) · Gut · doi:10.1136/gutjnl-2019-318325 · Cited by 93
Nucleome Dynamics during Retinal Development
Norrie, J. L., Lupo, M. S., Xu, B., Aldiri, I., Valentine, M. B., Putnam, D. K., Griffiths, L. M., Zhang, J., Johnson, D. A., Easton, J. B., et al. (2019) · Neuron · doi:10.1016/j.neuron.2019.08.002 · Cited by 87
INO80 governs superenhancer-mediated oncogenic transcription and tumor growth in melanomaPreprint
Zhou, B., Wang, L., Zhang, S., Bennett, B. D., He, F., Zhang, Y., Xiong, C., Han, L., Diao, L., Li, P., et al. (2016) · Genes & Development · doi:10.1101/gad.277178.115 · Cited by 92
“SEs play critical roles in driving the expression of cell identity genes (Hnisz et al. 2013; Loven et al. 2013; Whyte et al. 2013; Chipumuro et al. 2014).”
BackgroundGreuter, T., Yaqoob, U., Gan, C., Jalan-Sakrikar, N., Kostallari, E., Lu, J., Gao, J., Sun, L., Liu, M., Sehrawat, T. S., et al. (2022) · Journal of Hepatology · doi:10.1016/j.jhep.2022.03.029 · Cited by 92
Why the activity of a gene depends on its neighbors
Feuerborn, A., & Cook, P. R. (2015) · Trends in Genetics · doi:10.1016/j.tig.2015.07.001 · Cited by 91
Enhancer-Mediated Oncogenic Function of the Menin Tumor Suppressor in Breast Cancer
Dreijerink, K. M. A., Groner, A. C., Vos, E. S. M., Font‐Tello, A., Gu, L., Chi, D., Reyes, J. M., Cook, J., Lim, E., Lin, C. Y., et al. (2017) · Cell Reports · doi:10.1016/j.celrep.2017.02.025 · Cited by 96
“Indeed, about 50%of themenin/FOXA1/GATA3bound enhancers that displayed looping, including the sites near the ESR1, AGR2, and AGR3 genes, are within predicted super enhancer regions, indicating functional overlap of these meninbound sites with super enhancers (data not shown) (Hnisz et al., 2013).”
Chromosome territories and the global regulation of the genome
Fritz, A. J., Sehgal, N., Pliss, A., Xu, J., & Berezney, R. (2019) · Genes Chromosomes and Cancer · doi:10.1002/gcc.22732 · Cited by 102
“SEs have been implicated in cell-type specificity(281,282) and driving expression of oncogenes in cancer.(281,283) The advancement”
BackgroundClinical, Histopathological, and Molecular Diagnostics in Lethal Lung Developmental Disorders
Vincent, M., Karolak, J. A., Deutsch, G. H., Gambin, T., Popek, E. J., Isidor, B., Szafrański, P., Caignec, C. L., & Stankiewicz, P. (2019) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/rccm.201903-0495tr · Cited by 92
“This z200-kb interval overlaps the predicted regulatory elements identified in human fetal lung fibroblasts cell line (76).”
BackgroundDall’Agnese, A., Caputo, L., Nicoletti, C., di Iulio, J., Schmitt, A. D., Gatto, S., Diao, Y., Ye, Z., Forcato, M., Perera, R. J., et al. (2019) · Molecular Cell · doi:10.1016/j.molcel.2019.07.036 · Cited by 93
“While higher genomic structures appear to be generally conserved, chromatin interactions within TADs, subTADs and INs, could rather be cell-type specific and dynamic (Bonev et al., 2017; Dixon et al., 2015; Hnisz et al., 2013; Hnisz et al., 2016a; Javierre et al., 2016; Ji et al., 2016; Phanstiel et al., 2017; Remesei…”
BackgroundRavasio, R., Ceccacci, E., Nicosia, L., Hosseini, A., Rossi, P. L., Barozzi, I., Fornasari, L., Zuffo, R. D., Valente, S., Fioravanti, R., et al. (2020) · Science Advances · doi:10.1126/sciadv.aax2746 · Cited by 93
“Super-enhancers were identified as those above the inflection point of the H3K27ac signal versus enhancer rank (36).”
BackgroundIdentifying collagen VI as a target of fibrotic diseases regulated by CREBBP/EP300
Williams, L. M., McCann, F. E., Cabrita, M., Layton, T., Cribbs, A. P., Knezevic, B., Fang, H., Knight, J. C., Zhang, M., Fischer, R., et al. (2020) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2004281117 · Cited by 88
“Since both H3K27ac and EP300 (32, 46) demark the architecture of super enhancers in all cell types, this warrants further investigation using coactivators such as MED1 and other master transcription factors.”
BackgroundMethodAcetylated histone variant H2A.Z is involved in the activation of neo-enhancers in prostate cancer
Valdés‐Mora, F., Gould, C. M., Colino‐Sanguino, Y., Qu, W., Song, J. Z., Taylor, K. M., Buske, F. A., Statham, A. L., Nair, S. S., Armstrong, N. J., et al. (2017) · Nature Communications · doi:10.1038/s41467-017-01393-8 · Cited by 92
Laying a solid foundation for Manhattan – ‘setting the functional basis for the post-GWAS era’
Zhang, X., Bailey, S. D., & Lupien, M. (2014) · Trends in Genetics · doi:10.1016/j.tig.2014.02.006 · Cited by 95
Emergence of the Noncoding Cancer Genome: A Target of Genetic and Epigenetic Alterations
Zhou, S., Treloar, A. E., & Lupien, M. (2016) · Cancer Discovery · doi:10.1158/2159-8290.cd-16-0745 · Cited by 89
Mitchell, A., Javidfar, B., Pothula, V., Ibi, D., Shen, E., Peter, C. J., Bicks, L. K., Fehr, T., Jiang, Y., Brennand, K., et al. (2017) · Molecular Psychiatry · doi:10.1038/mp.2016.254 · Cited by 88
“…PFC neurons showed significant enrichment for eight motifs (Supplemental Table 12), when using the total set of N=342 brain-specific super-enhancers 27 as background (P 0.05, right-tailed binomial significance test, corrected by the total number of motifs predicted = evalue, reported as weight…”
InfluentialYi, M., Tan, Y., Wang, L., Cai, J., Li, X., Zeng, Z., Xiong, W., Li, X., Li, X., Tan, P., et al. (2020) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-020-03539-2 · Cited by 89
“Remarkably, a large set of ΔNp63α-occupied regions are characterized as super enhancers (SE) [82], which are believed to drive oncogene expression in multiple cancers [84, 85].”
BackgroundBRD4 orchestrates genome folding to promote neural crest differentiation
Linares-Saldana, R., Kim, W., Bolar, N. A., Zhang, H., Koch-Bojalad, B. A., Yoon, S., Shah, P. P., Karnay, A. M., Park, D. S., Luppino, J. M., et al. (2021) · Nature Genetics · doi:10.1038/s41588-021-00934-8 · Cited by 91
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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