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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]
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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“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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“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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Citations
Cites
Hallmarks of Cancer: The Next Generation
Hanahan, D., & Weinberg, R. A. (2011) · Cell · doi:10.1016/j.cell.2011.02.013 · Cited by 66,590
Ultrafast and memory-efficient alignment of short DNA sequences to the human genome.
Langmead, B., Trapnell, C., Pop, M., & Salzberg, S. L. (2009) · Genome Biology · doi:10.1186/gb-2009-10-3-r25 · Cited by 21,849
Model-based Analysis of ChIP-Seq (MACS)
Zhang, Y., Liu, T., Meyer, C. A., Eeckhoute, J., Johnson, D. S., Bernstein, B. E., Nusbaum, C., Myers, R. M., Brown, M., Li, W., et al. (2008) · Genome Biology · doi:10.1186/gb-2008-9-9-r137 · Cited by 18,386
An integrated encyclopedia of DNA elements in the human genome
The ENCODE Project Consortium (2012) · Nature · doi:10.1038/nature11247 · Cited by 18,072
A genetic model for colorectal tumorigenesis
Fearon, E. R., & Vogelstein, B. (1990) · Cell · doi:10.1016/0092-8674(90)90186-i · Cited by 12,132
TopHat: discovering splice junctions with RNA-Seq
Trapnell, C., Pachter, L. S., & Salzberg, S. L. (2009) · Bioinformatics · doi:10.1093/bioinformatics/btp120 · Cited by 11,682
The Human Genome Browser at UCSC
Kent, W. J., Sugnet, C. W., Furey, T. S., Roskin, K. M., Pringle, T. H., Zahler, A. M., & Haussler, A. D. (2002) · Genome Research · doi:10.1101/gr.229102 · Cited by 10,400
Vogelstein, B., Papadopoulos, N., Velculescu, V. E., Zhou, S., Diaz, L. A., & Kinzler, K. W. (2013) · Science · doi:10.1126/science.1235122 · Cited by 7,863
Topological domains in mammalian genomes identified by analysis of chromatin interactions
Dixon, J. R., Selvaraj, S., Yue, F., Kim, A., Li, Y., Shen, Y., Hu, M., Liu, J. S., & Ren, B. (2012) · Nature · doi:10.1038/nature11082 · Cited by 6,829
Core Transcriptional Regulatory Circuitry in Human Embryonic Stem Cells
Boyer, L. A., Lee, T. I., Cole, M. F., Johnstone, S. E., Levine, S. S., Zucker, J. P., Guenther, M. G., Kumar, R. M., Murray, H. L., Jenner, R. G., et al. (2005) · Cell · doi:10.1016/j.cell.2005.08.020 · Cited by 4,505
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Items 601–700 of 1,018
Zhang, H., Zhang, N., Liu, Y., Su, P., Liang, Y., Li, Y., Wang, X., Chen, T., Song, X., Sang, Y., et al. (2021) · Cancer Research · doi:10.1158/0008-5472.can-21-1188 · Cited by 92
Aune, T. M., Crooke, P. S., Patrick, A. E., Tossberg, J. T., Olsen, N. J., & Spurlock, C. F. (2017) · Journal of Autoimmunity · doi:10.1016/j.jaut.2017.03.014 · Cited by 90
Hoang, P. H., Dobbins, S. E., Cornish, A. J., Chubb, D., Law, P., Kaiser, M., & Houlston, R. S. (2018) · Leukemia · doi:10.1038/s41375-018-0103-3 · Cited by 87
“defined cancer hallmarks [58] and in signaling pathways involved MM, including NIK/NF-κB signaling, MAPK signaling, B-cell proliferation, and B-cell activation and”
BackgroundKim, S. Y., Zhang, X., Schiattarella, G. G., Altamirano, F. J., Ramos, T. A. R., French, K. M., Jiang, N., Szweda, P. A., Evers, B. M., May, H. I., et al. (2020) · Circulation · doi:10.1161/circulationaha.120.047239 · Cited by 90
Molecular and genetic insights into human ovarian aging from single-nuclei multi-omics analyses
Jin, C., Wang, X., Yang, J., Kim, S.-S., Hudgins, A. D., Gamliel, A., Pei, M., Contreras, D., Devos, M., Guo, Q., et al. (2024) · Nature Aging · doi:10.1038/s43587-024-00762-5 · Cited by 107
“Recent studies show that non-coding GWAS variants are significantly enriched in cell-type-specific transcriptional regulatory elements, such as enhancers 9–11 .”
MLL4 prepares the enhancer landscape for Foxp3 induction via chromatin looping
Placek, K., Hu, G., Cui, K., Zhang, D., Ding, Y., Lee, J., Jang, Y., Wang, C., Konkel, J. E., Song, J., et al. (2017) · Nature Immunology · doi:10.1038/ni.3812 · Cited by 95
Quevedo, M., Meert, L., Dekker, M. R., Dekkers, D. H. W., Brandsma, J. H., van den Berg, D. L. C., Özgür, Z., van IJcken, W. F. J., Demmers, J., Fornerod, M. W. J., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-10502-8 · Cited by 95
Lhoumaud, P., Badri, S., Rodriguez-Hernaez, J., Sakellaropoulos, T., Sethia, G., Kloetgen, A., Cornwell, M., Bhattacharyya, S., Ay, F., Bonneau, R., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-12811-4 · Cited by 92
Oncogenic super-enhancer formation in tumorigenesis and its molecular mechanisms
Jia, Q., Chen, S., Tan, Y., Li, Y., & Tang, F. (2020) · Experimental & Molecular Medicine · doi:10.1038/s12276-020-0428-7 · Cited by 92
Moudgil, A., Wilkinson, M., Chen, X., He, J., Cammack, A. J., Vasek, M. J., Lagunas, T., Qi, Z., Lalli, M. A., Guo, C., et al. (2020) · Cell · doi:10.1016/j.cell.2020.06.037 · Cited by 80
From start to end: Phase separation and transcriptional regulation
Liu, P., Li, E., & Xu, L. (2020) · Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms · doi:10.1016/j.bbagrm.2020.194641 · Cited by 86
Genetic Variation in Enhancers Modifies Cardiomyopathy Gene Expression and Progression
Gacita, A. M., Fullenkamp, D. E., Ohiri, J. C., Pottinger, T. D., Puckelwartz, M. J., Nóbrega, M. A., & McNally, E. M. (2021) · Circulation · doi:10.1161/circulationaha.120.050432 · Cited by 90
Roles of non-canonical structures of nucleic acids in cancer and neurodegenerative diseases
Tateishi‐Karimata, H., & Sugimoto, N. (2021) · Nucleic Acids Research · doi:10.1093/nar/gkab580 · Cited by 87
“Moreover, transcriptional coactivator proteins form droplets at super enhancers, which regulate genes, thereby influencing cell identity and function (133), especially in cancer-related genes including those related to diffuse large B cell lymphoma (134,135).”
BackgroundLi, Y., Liang, J. H., Ozer, A., Leung, A. K.-Y., Lis, J. T., & Yu, H. (2022) · Nature Biotechnology · doi:10.1038/s41587-022-01211-7 · Cited by 84
Kerns, S. L., Dorling, L., Fachal, L., Bentzen, S. M., Pharoah, P. D. P., Barnes, D. R., Gómez‐Caamaño, A., Carballo, A. M., Dearnaley, D. P., Peleteiro, P., et al. (2016) · EBioMedicine · doi:10.1016/j.ebiom.2016.07.022 · Cited by 90
“The significant SNPs lie in non-coding regions, as is common in GWAS where ~64% of identified SNPs lie in enhancer regions (Hnisz et al., 2013).”
BackgroundFunctional Architectures of Local and Distal Regulation of Gene Expression in Multiple Human Tissues
Liu, X., Finucane, H. K., Gusev, A., Bhatia, G., Gazal, S., O’Connor, L. J., Bulik-Sullivan, B. K., Wright, F. A., Sullivan, P. F., Neale, B. M., et al. (2017) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2017.03.002 · Cited by 87
Wong, R. W. J., Ngoc, P. C. T., Leong, W. Z., Yam, A. W. Y., Zhang, T., Asamitsu, K., Iida, S., Okamoto, T., Ueda, R., Gray, N. S., et al. (2017) · Blood · doi:10.1182/blood-2017-06-792184 · Cited by 90
“Super-enhancers are also often enriched at cancer gene loci in various malignancies.(24,25,27,28) Although the biological significance of super-enhancer still remains controversial, this concept is useful as a marker to identify critical genes that are highly expressed and uniquely required for normal development or p…”
West, J. A., Cook, A., Alver, B., Stadtfeld, M., Deaton, A., Hochedlinger, K., Park, P. J., Tolstorukov, M., & Kingston, R. (2014) · Nature Communications · doi:10.1038/ncomms5719 · Cited by 95
Xing, R., Zhou, Y., Yu, J., Yu, Y., Nie, Y., Luo, W., Yang, C., Xiong, T., Wu, W. K. K., Li, Z., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-09644-6 · Cited by 85
Illuminating the noncoding genome in cancer
Zhang, X., & Meyerson, M. M. (2020) · Nature Cancer · doi:10.1038/s43018-020-00114-3 · Cited by 86
González, A. J., Setty, M. N., & Leslie, C. S. (2015) · Nature Genetics · doi:10.1038/ng.3402 · Cited by 85
“10–11, 13–14), suggesting that a subpopulation of these DHSs are not active transcriptional enhancers.”
InfluentialOber-Reynolds, B., Wang, C., Ko, J. M., Rios, E. J., Aasi, S. Z., Davis, M. M., Oro, A. E., & Greenleaf, W. J. (2023) · Nature Genetics · doi:10.1038/s41588-023-01445-4 · Cited by 83
“We compared these HRGs with a dataset of previously identified superenhancer-associated genes from a variety of tissues and cell lines 35 .”
InfluentialTranscriptional and epigenetic networks of helper T and innate lymphoid cells
Shih, H., Sciumè, G., Poholek, A. C., Vahedi, G., Hirahara, K., Villarino, A. V., Bonelli, M. M., Bosselut, R., Kanno, Y., Muljo, S. A., et al. (2014) · Immunological Reviews · doi:10.1111/imr.12208 · Cited by 91
Miao, L., Tang, Y., Bonneau, A. R., Chan, S. H., Kojima, M. L., Pownall, M. E., Vejnar, C. E., Gao, F., Krishnaswamy, S., Hendry, C., et al. (2022) · Molecular Cell · doi:10.1016/j.molcel.2022.01.024 · Cited by 85
“, 2008) to promote Pol II recruitment and transcriptional initiation and elongation in ES cells (Hnisz et al., 2013; Whyte et al., 2013).”
BackgroundLiu, H., Liu, X., Zhang, S., Lv, J., Li, S., Shang, S., Jia, S., Wei, Y., Wang, F., Su, J., et al. (2015) · Nucleic Acids Research · doi:10.1093/nar/gkv1332 · Cited by 85
“, who identified superenhancers from 86 human cell and tissue samples based on the H3K27ac ChIP-Seq data (22).”
InfluentialBaldauf, M. C., Orth, M. F., Dallmayer, M., Marchetto, A., Gerke, J. S., Rubío, R. A., Kıran, M. M., Musa, J., Knott, M. M. L., Ohmura, S., et al. (2017) · Oncotarget · doi:10.18632/oncotarget.20098 · Cited by 93
“Super-enhancers are often found near genes that have cell type-specific functions and contribute to cell identity [28, 29].”
BackgroundThe BET Family Member BRD4 Interacts with OCT4 and Regulates Pluripotency Gene Expression
Wu, T., Pinto, H. B., Kamikawa, Y. F., & Donohoe, M. E. (2015) · Stem Cell Reports · doi:10.1016/j.stemcr.2015.01.012 · Cited by 85
An Important Role for DNMT3A-Mediated DNA Methylation in Cardiomyocyte Metabolism and Contractility
Madsen, A., Höppner, G., Krause, J., Hirt, M. N., Laufer, S. D., Schweizer, M., Tan, W. L. W., Mosqueira, D., Anene-Nzelu, C. G., Lim, I. Y., et al. (2020) · Circulation · doi:10.1161/circulationaha.119.044444 · Cited by 91
“16,42 Moreover, methylation changes in enhancers involved in MYH7 gene regulation 43 contribute to the altered expression.”
Modeling cis-regulation with a compendium of genome-wide histone H3K27ac profilesPreprint
Wang, S., Zang, C., Xiao, T., Fan, J., Mei, S., Qin, Q., Wu, Q., Li, X., Xu, K., He, H. H., et al. (2016) · Genome Research · doi:10.1101/gr.201574.115 · Cited by 81
“It has been suggested that superenhancers regulate key tissue-specific genes (Hnisz et al. 2013).”
InfluentialTFAP2 paralogs regulate melanocyte differentiation in parallel with MITF
Seberg, H. E., Van Otterloo, E., Loftus, S. K., Liu, H., Bonde, G., Sompallae, R., Gildea, D. E., Santana, J. F., Manak, J. R., Pavan, W. J., et al. (2017) · PLOS Genetics · doi:10.1371/journal.pgen.1006636 · Cited by 85
“Following published methods, we used H3K27ac data to identify 652 SEs in human primary melanocytes [85] (S7 Fig).”
BackgroundMethodImmunogenetics of rheumatoid arthritis: Understanding functional implications
Messemaker, T. C., Huizinga, T. W. J., & Kurreeman, F. A. S. (2015) · Journal of Autoimmunity · doi:10.1016/j.jaut.2015.07.007 · Cited by 92
CBP/p300 acetyltransferase activity in hematologic malignancies
Dutta, R., Tiu, B. C., & Sakamoto, K. M. (2016) · Molecular Genetics and Metabolism · doi:10.1016/j.ymgme.2016.06.013 · Cited by 84
Dooley, K. E., Warburton, A., & McBride, A. A. (2016) · mBio · doi:10.1128/mbio.01446-16 · Cited by 86
“Binding of transcription factors, cofactors, and chromatin regulators is enriched at super-enhancers; specifically, super-enhancers can be identified by a high density of mediator, acetylated H3K27, and Brd4 (18, 19).”
InfluentialOchi, Y., Kon, A., Sakata, T., Nakagawa, M. M., Nakazawa, N., Kakuta, M., Kataoka, K., Koseki, H., Nakayama, M., Morishita, D., et al. (2020) · Cancer Discovery · doi:10.1158/2159-8290.cd-19-0982 · Cited by 86
“SEassociated genes identified in human normal HSPCs (35) were marginally downregulated in cohesin/STAG2-mutated MDS samples, as compared with TE-associated genes; however, this trend was less clear in AML samples (Supplementary Fig.”
MethodResultInfluentialThe emerging role of super enhancer-derived noncoding RNAs in human cancer
Wang, Y., Nie, H., He, X., Liao, Z., Zhou, Y., Zhou, J., & Ou, C. (2020) · Theranostics · doi:10.7150/thno.49168 · Cited by 85
“SEs regulate the malignant biological phenotype of tumors via these mechanisms [47-49].”
BackgroundSengupta, D., Kannan, A., Kern, M., Moreno, M. A., Vural, E. A., Stack, B. C., Suen, J. Y., Tackett, A. J., & Gao, L. (2015) · Epigenetics · doi:10.1080/15592294.2015.1034416 · Cited by 87
Li, M. J., Yan, B., Sham, P. C., & Wang, J. (2014) · Briefings in Bioinformatics · doi:10.1093/bib/bbu018 · Cited by 89
“Many continuous genomic loci that can recruit the binding of core TFs and function as super enhancers have been identified [148, 149].”
BackgroundVijayakrishnan, J., Kumar, R., Henrion, M., Moorman, A. V., Rachakonda, P. S., Hosen, M. I., Filho, M. I. D. S., Holroyd, A. K., Dobbins, S. E., Koehler, R., et al. (2016) · Leukemia · doi:10.1038/leu.2016.271 · Cited by 86
RUNX1 is required for oncogenic Myb and Myc enhancer activity in T-cell acute lymphoblastic leukemia
Choi, A., Illendula, A., Pulikkan, J. A., Roderick, J. E., Tesell, J., Yu, J., Hermance, N. M., Zhu, L. J., Castilla, L. H., Bushweller, J. H., et al. (2017) · Blood · doi:10.1182/blood-2017-03-775536 · Cited by 88
Zhao, X., Ren, Y., Lawlor, M. A., Shah, B. D., Park, P. M. C., Lwin, T., Wang, X., Liu, K., Wang, M. Y., Gao, J., et al. (2019) · Cancer Cell · doi:10.1016/j.ccell.2019.04.005 · Cited by 88
Phase Separation of Epstein-Barr Virus EBNA2 and Its Coactivator EBNALP Controls Gene Expression
Qiu, P., Wang, L., Qin, Z., Wang, J., Zheng, X., Wei, L., Zhang, X., Zhang, X., Liu, C., Li, Z., et al. (2020) · Journal of Virology · doi:10.1128/jvi.01771-19 · Cited by 84
Super-enhancers: a new frontier for epigenetic modifiers in cancer chemoresistance
Li, G., Qu, Q., Qi, T.-T., Teng, X.-Q., Zhu, H., Wang, J., Lu, Q., & Qu, J. (2021) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-021-01974-y · Cited by 89
Signal-Dependent Recruitment of BRD4 to Cardiomyocyte Super-Enhancers Is Suppressed by a MicroRNA
Stratton, M. S., Lin, C. Y., Anand, P., Tatman, P. D., Ferguson, B. S., Wickers, S. T., Ambardekar, A. V., Sucharov, C. C., Bradner, J. E., Haldar, S. M., et al. (2016) · Cell Reports · doi:10.1016/j.celrep.2016.06.074 · Cited by 86
“…enhancers called super-enhancers (SEs) (Brown et al., 2014; Chapuy et al., 2013; Di Micco et al., 2014; Lovén et al., 2013), which signal via long-range genomic interactions to regulate state-specific transcription programs from core promoters (Hnisz et al., 2013, 2015; Whyte et al., 2013).”
BackgroundJoshi, S., Davidson, G., Gras, S. L., Watanabe, S., Braun, T. W., Mengus, G., & Davidson, I. (2017) · PLoS Genetics · doi:10.1371/journal.pgen.1006600 · Cited by 84
Soibam, B. (2017) · RNA · doi:10.1261/rna.061317.117 · Cited by 84
“Super-enhancers are clusters of enhancers that are characterized by high levels of Mediator binding and associated primarily with tissue-specific genes (Hnisz et al. 2013; Pott and Lieb 2014; Khan and Zhang 2016).”
BackgroundMethodInfluentialDynamic lineage priming is driven via direct enhancer regulation by ERK
Hamilton, W. B., Mosesson, Y., Monteiro, R. S., Emdal, K. B., Knudsen, T. E., Francavilla, C., Barkai, N., Olsen, J. V., & Brickman, J. M. (2019) · Nature · doi:10.1038/s41586-019-1732-z · Cited by 80
Superenhancer reprogramming drives a B-cell–epithelial transition and high-risk leukemiaPreprint
Hu, Y., Zhang, Z., Kashiwagi, M., Yoshida, T., Joshi, I., Jena, N., Somasundaram, R., Emmanuel, A. O., Sigvardsson, M., Fitamant, J., et al. (2016) · Genes & Development · doi:10.1101/gad.283762.116 · Cited by 86
“Superen-hancers are defined as clusters of binding sites for master transcription regulators that are highly enriched for active histone modifications and the Mediator complex (Hnisz et al. 2013, 2015; Whyte et al. 2013).”
Chromatin dependencies in cancer and inflammation
Marazzi, I., Greenbaum, B. D., Low, D. H. P., & Guccione, E. (2018) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm.2017.113 · Cited by 80
Genome-wide significant risk associations for mucinous ovarian carcinoma
Kelemen, L. E., Lawrenson, K., Lee, J. M., Spindler, T. J., Lee, A. W., Pearce, C. L., Pike, M. C., Ramus, S. J., Wu, A. H., Gayther, S. A., et al. (2015) · Nature Genetics · doi:10.1038/ng.3336 · Cited by 81
Dynamic Enhancer DNA Methylation as Basis for Transcriptional and Cellular Heterogeneity of ESCs
Song, Y., van den Berg, P. R., Markoulaki, S., Soldner, F., Dall’Agnese, A., Henninger, J. E., Drotar, J., Rosenau, N., Cohen, M. A., Young, R. A., et al. (2019) · Molecular Cell · doi:10.1016/j.molcel.2019.06.045 · Cited by 84
“The Sox2 SE harbors multiple enrichment sites for the master TFs OCT4 and NANOG in ESCs (Hnisz et al., 2013) (Figure 4A, top).”
BackgroundSelf-citationBroad domains of histone H3 lysine 4 trimethylation in transcriptional regulation and disease
Park, S., Kim, G. W., Kwon, S. H., & Lee, J. (2020) · FEBS Journal · doi:10.1111/febs.15219 · Cited by 88
Casalino, L., & Verde, P. (2020) · Genes · doi:10.3390/genes11080922 · Cited by 83
“Recent genome-wide analyses (bisulfite sequencing of 13 human samples and further validation on almost 700 samples from TCGA (the Cancer Genome Atlas) have been focused on super-enhancer regions, defined as clusters of transcriptional enhancers exhibiting maximal levels of histone H3K27 acetylation and BRD4 recruitmen…”
BackgroundEpigenetic modulation of type-1 diabetes via a dual effect on pancreatic macrophages and β cells
Fu, W., Farache, J., Clardy, S. M., Hattori, K., Mander, P. K., Lee, K. C., Rioja, I., Weissleder, R., Prinjha, R. K., Benoist, C. O., et al. (2014) · eLife · doi:10.7554/elife.04631 · Cited by 84
Schmidt, S. F., Larsen, B. D., Loft, A., Nielsen, R., Madsen, J. G. S., & Mandrup, S. (2015) · Genome Research · doi:10.1101/gr.188300.114 · Cited by 83
“Based on the central role of super-enhancers in gene repression by TNF in SGBS adipocytes, combined with results showing that super-enhancers are highly cell-type specific (Hnisz et al. 2013; Whyte et al. 2013; Loft et al. 2015), we hypothesized that TNF treatment should lead to acute repression of highly distinct gen…”
BackgroundResultInfluentialHeinemann, A., Cullinane, C. M., Paoli‐Iseppi, R. D., Wilmott, J. S., Gunatilake, D., Madore, J., Strbenac, D., Yang, J. Y. H., Gowrishankar, K., Tiffen, J. C., et al. (2015) · Oncotarget · doi:10.18632/oncotarget.4242 · Cited by 82
“BET proteins on the other hand are components of complexes that target transcription factors to acetylated histones particularly at sites of so called super enhancers [20, 21].”
BackgroundNon-coding somatic mutations converge on the PAX8 pathway in ovarian cancer
Corona, R. I., Seo, J.-H., Lin, X., Hazelett, D. J., Reddy, J., Fonseca, M. A., Abbasi, F., Lin, Y. G., Mhawech-Fauceglia, P. Y., Shah, S. P., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-15951-0 · Cited by 82
Developmental and evolutionary dynamics of cis-regulatory elements in mouse cerebellar cells
Sarropoulos, I., Sepp, M., Frömel, R., Leiss, K., Trost, N., Leushkin, E. V., Okonechnikov, K., Joshi, P. K., Giere, P., Kutscher, L. M., et al. (2021) · Science · doi:10.1126/science.abg4696 · Cited by 79
Current challenges in understanding the role of enhancers in disease
Zaugg, J. B., Sahlén, P., Andersson, R., Alberich-Jordà, M., de Laat, W. L., Deplancke, B., Ferrer, J. P., Mandrup, S., Natoli, G., Plewczyński, D., et al. (2022) · Nature Structural & Molecular Biology · doi:10.1038/s41594-022-00896-3 · Cited by 86
“Nature Structural and Molecular Biology, 29(12), 1148-1158.”
Su, T., Zhang, N., Wang, T., Zeng, J., Li, W., Han, L., & Yang, M. (2023) · Cancer Research · doi:10.1158/0008-5472.can-23-0544 · Cited by 82
Chan, A., & Chen, C.-W. D. (2019) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2019.00081 · Cited by 83
“Superenhancers are large clusters of transcriptional enhancers packed with TFs, cofactors, transcription apparatus, and chromatin regulators such as BRD4 (Hnisz et al., 2013).”
BackgroundLin, L., Huang, M., Shi, X., Mayakonda, A., Hu, K., Jiang, Y., Guo, X., Chen, L., Pang, B., Doan, N., et al. (2018) · Nucleic Acids Research · doi:10.1093/nar/gky1207 · Cited by 84
“Super-enhancer elements are frequently associated with and regulated by master transcription factors in normal cell development (8,23).”
BackgroundMethodThe threat of programmed DNA damage to neuronal genome integrity and plasticity
Caldecott, K. W., Ward, M. E., & Nussenzweig, A. (2022) · Nature Genetics · doi:10.1038/s41588-021-01001-y · Cited by 80
Sokolik, C., Liu, Y., Bauer, D. P., McPherson, J., Broeker, M., Heimberg, G., Qi, L. S., Sivak, D. A., & Thomson, M. W. (2015) · Cell Systems · doi:10.1016/j.cels.2015.08.001 · Cited by 80
“However, metazoans present a quandary: instead of negative feedback, stem cell regulatory networks are dominated by positive feedback regulation (Fong and Tapscott, 2013; Hnisz et al., 2013; Jaenisch and Young, 2008; Kueh et al., 2013; Niwa, 2007; Whyte et al., 2013).”
BackgroundInfluentialFunctional Enhancers As Master Regulators of Tissue-Specific Gene Regulation and Cancer Development
Ko, J. Y., Oh, S., & Yoo, K. H. (2017) · Molecules and Cells · doi:10.14348/molcells.2017.0033 · Cited by 83
“Cells 2017; 40(3): 169-177 169”
Gerlach, D., Tontsch-Grunt, U., Baum, A., Popow, J., Scharn, D., Hofmann, M. H., Engelhardt, H., Kaya, O., Beck, J., Schweifer, N., et al. (2018) · Oncogene · doi:10.1038/s41388-018-0150-2 · Cited by 82
“One hypothesis that has been proposed for several years, but never formally proven, is that the sensitivity of cancer cells to BET inhibition is mediated by the repression of cancer-specific super-enhancer-driven oncogenes [6, 7, 26, 28].”
BackgroundCao, F., Fang, Y., Tan, H. K., Goh, Y., Choy, J. Y. H., Koh, B. T. H., Hao Tan, J., Bertin, N., Ramadass, A., Hunter, E., et al. (2017) · Scientific Reports · doi:10.1038/s41598-017-02257-3 · Cited by 80
“We annotated the genes using two different databases: (1) the lists of oncogenes and tumor suppressor genes from Tumor Suppressor and Oncogene (TUSON) Explorer19, a computational method that analyzed mutational signatures in tumor-normal pairs to predict how likely a gene is a tumor suppressor gene or an oncogene; (2)…”
BackgroundMethodZhuang, Q., Li, W., Benda, C., Huang, Z., Ahmed, T., Liu, P., Guo, X., Ibañez, D. P., Luo, Z., Zhang, M., et al. (2018) · Nature Cell Biology · doi:10.1038/s41556-018-0047-x · Cited by 77
Targeting DNA Damage Response in Prostate and Breast Cancer
Wengner, A. M., Scholz, A., & Haendler, B. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21218273 · Cited by 81
“They are highly loaded with the mediator complex and the bromodomain protein BRD4, and they form long-range interactions by chromosomal looping and assemble into local transcription factories [73,75,76].”
BackgroundHijacking of transcriptional condensates by endogenous retroviruses
Asimi, V., Kumar, A. S., Niskanen, H., Riemenschneider, C., Hetzel, S., Naderi, J., Fasching, N., Popitsch, N. P., Du, M., Kretzmer, H., et al. (2022) · Nature Genetics · doi:10.1038/s41588-022-01132-w · Cited by 79
Self-citationZhang, J., Pan, W., Zhang, Y., Tan, M.-Y., Yin, Y., Li, Y.-M., Zhang, L., Han, L.-H., Bai, J.-K., Jiang, T., et al. (2022) · Theranostics · doi:10.7150/thno.77243 · Cited by 75
“discovered a new class of gene regulatory elements called "superenhancers," characterized by clusters of adjacent large enhancers that drive the specific expression of genes [186].”
BackgroundChromosome contacts in activated T cells identify autoimmune disease candidate genes
Burren, O. S., Rubio García, A., Javierre, B.-M., Rainbow, D. B., Cairns, J., Cooper, N. J., Lambourne, J. J., Schofield, E., Castro Dopico, X., Ferreira, R. C., et al. (2017) · Genome Biology · doi:10.1186/s13059-017-1285-0 · Cited by 80
“Integration of GWAS signals with cell-specific chromatin marks has highlighted the role of regulatory variation in immune cells [7], and in particular CD4 T cells, in autoimmune diseases [8].”
BackgroundResultWaldmann, T., Rempel, E., Balmer, N. V., König, A., Kolde, R., Gaspar, J. A., Henry, M., Hescheler, J., Sachinidis, A., Rahnenführer, J., et al. (2014) · Chemical Research in Toxicology · doi:10.1021/tx400402j · Cited by 106
Targeting MYC in cancer therapy: RNA processing offers new opportunities
Koh, C. M., Sabò, A., & Guccione, E. (2016) · BioEssays · doi:10.1002/bies.201500134 · Cited by 86
“Transcription of the MYC gene is controlled in a complex manner, by the action of numerous transcriptional regulators [67], as well as enhancers [68].”
BackgroundIotchkova, V., Huang, J., Morris, J. A., Jain, D., Barbieri, C., Walter, K., Min, J. L., Chen, L., Astle, W. J., Cocca, M., et al. (2016) · Nature Genetics · doi:10.1038/ng.3668 · Cited by 80
Transcriptional control by enhancers and enhancer RNAs
Lewis, M. W., Shen, L., & Franco, H. L. (2019) · Transcription · doi:10.1080/21541264.2019.1695492 · Cited by 84
“These SEs drive high levels of transcription and are strongly proposed to be cell fate determinants that dictate cell type-specific gene expression [55,63,64].”
BackgroundDifferential contribution of p300 and CBP to regulatory element acetylation in mESCs
Martire, S., Nguyen, J., Sundaresan, A., & Banaszynski, L. A. (2020) · BMC Molecular and Cell Biology · doi:10.1186/s12860-020-00296-9 · Cited by 82
LARP7 suppresses P-TEFb activity to inhibit breast cancer progression and metastasis
Ji, X., Lu, H., Zhou, Q., & Luo, K. (2014) · eLife · doi:10.7554/elife.02907 · Cited by 79
Enhancer and super‐enhancer: Positive regulators in gene transcription
Peng, Y., & Zhang, Y. (2018) · Animal Models and Experimental Medicine · doi:10.1002/ame2.12032 · Cited by 78
“occupied by the master regulators and mediators, which is speculated to act as switches to determine cell identity and fate.(116,117) This notion was first described as genomic regions with high levels of five”
BackgroundRNA Targets Ribogenesis Factor WDR43 to Chromatin for Transcription and Pluripotency Control
Bi, X., Xu, Y., Li, T., Li, X., Li, W., Shao, W., Wang, K., Zhan, G., Wu, Z., Liu, W., et al. (2019) · Molecular Cell · doi:10.1016/j.molcel.2019.05.007 · Cited by 79
Is a super-enhancer greater than the sum of its parts?
Dukler, N., Gulko, B., Huang, Y.-F., & Siepel, A. (2017) · Nature Genetics · doi:10.1038/ng.3759 · Cited by 79
Koues, O. I., Kowalewski, R., Chang, L., Pyfrom, S., Schmidt, J. A., Luo, H., Sandoval, L., Hughes, T. B., Bednarski, J. J., Cashen, A. F., et al. (2014) · Immunity · doi:10.1016/j.immuni.2014.12.021 · Cited by 81
Pan-cancer analysis on microRNA-associated gene activation
Tan, H., HUANG, S. H., Zhang, Z., Qian, X., Sun, P., & Zhou, X. (2019) · EBioMedicine · doi:10.1016/j.ebiom.2019.03.082 · Cited by 79
“In the established ROSE (Rank Ordering of Super-Enhancers) pipeline [53], super-enhancers were identified based on the ChIP-seq signal of a typical enhancer marker histone H3 lysine 27 acetylation (H3K27ac).”
BackgroundTan, Y., Wang, X., Song, H., Zhang, Y., Zhang, R., Li, S., Jin, W. Y., Chen, S., Fang, H., Zhu, C. H., et al. (2020) · Blood · doi:10.1182/blood.2020005698 · Cited by 80
Epigenetic Regulation of Inflammatory Signaling and Inflammation-Induced Cancer
Tan, S. Y. X., Zhang, J., & Tee, W. (2022) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2022.931493 · Cited by 86
“Super-Enhancers Super-enhancers (SEs) are active transcriptional hubs that consist of multiple enhancer elements densely bound by TFs and coactivators, especially the Mediator complex, and they exert crucial functions during cell fate specification and oncogenesis (Hnisz et al., 2013; Loven et al., 2013; Whyte et al.,…”
BackgroundAn atlas of regulatory elements in chicken: A resource for chicken genetics and genomics
Pan, Z., Wang, Y., Wang, M., Wang, Y., Zhu, X., Gu, S. V., Zhong, C., An, L., Shan, M., Damas, J., et al. (2023) · Science Advances · doi:10.1126/sciadv.ade1204 · Cited by 85
“Super-enhancers, which are clusters of enhancers in close genomic proximity (within 12.5 kb) that bind various transcription factors, are proposed to play key roles in the control of cell identity, and their dysfunction may cause diseases ( 22 , 23 ).”
InfluentialThe role of the dynamic epigenetic landscape in senescence: orchestrating SASP expression
Dasgupta, N., Arnold, R., Equey, A., Gandhi, A., & Adams, P. D. (2024) · npj Aging · doi:10.1038/s41514-024-00172-2 · Cited by 93
“Super-enhancers (SEs) consist of large clusters of neighboring enhancers with high-fold enhancer activity, which collectively drive cell-type-speci fi c gene expression 54 .”
BackgroundNorthcott, P. A., Pfister, S. M., & Jones, D. (2015) · The Lancet Oncology · doi:10.1016/s1470-2045(14)71206-9 · Cited by 80
Sungalee, S., Liu, Y., Lambuta, R. A., Katanayeva, N., Donaldson Collier, M., Tavernari, D., Roulland, S., Ciriello, G., & Oricchio, E. (2021) · Nature Genetics · doi:10.1038/s41588-021-00842-x · Cited by 70
Yang, H., Schramek, D., Adam, R. C., Keyes, B. E., Wang, P., Zheng, D., & Fuchs, E. V. (2015) · eLife · doi:10.7554/elife.10870 · Cited by 77
“…cancer cell lines in vitro and their normal whole tissue (e.g. MCF7 breast cancer cell line and mammary epithelium), increasing evidence underscores the importance of SEs in cancers (Parker et al., 2013; Hnisz et al., 2013; Lovén et al., 2013; Chapuy et al., 2013; Chipumuro et al., 2014).”
BackgroundMethodInfluentialLee, D. J., & Zeidner, J. F. (2019) · Expert Opinion on Investigational Drugs · doi:10.1080/13543784.2019.1678583 · Cited by 78
“P-TEFb exists in a super-enhancer complex and phosphorylates RNA polymerase II, which thereby activates global transcription elongation of important genes involved in cell proliferation and survival such as MYC and MCL-1 (Figure 1) [26,27].”
BackgroundInducible transcriptional condensates drive 3D genome reorganization in the heat shock response
Chowdhary, S., Kainth, A. S., Paracha, S., Gross, D. S., & Pincus, D. (2022) · Molecular Cell · doi:10.1016/j.molcel.2022.10.013 · Cited by 80
From CNS stem cells to neurons and glia: Sox for everyone
Reiprich, S., & Wegner, M. (2014) · Cell and Tissue Research · doi:10.1007/s00441-014-1909-6 · Cited by 76
NFIB overexpression cooperates with Rb/p53 deletion to promote small cell lung cancer
Wu, N., Jia, D., Ibrahim, A. H., Bachurski, C. J., Gronostajski, R. M., & MacPherson, D. P. (2016) · Oncotarget · doi:10.18632/oncotarget.11583 · Cited by 77
Ge, Y., Paisie, T. K., Newman, J. R. B., McIntyre, L. M., & CONCANNON, P. J. (2017) · Diabetes · doi:10.2337/db16-1023 · Cited by 77
“Previous studies showed that rs11203203 and rs80054410 are located in a putative enhancer or superenhancer region in human primary CD4 T cells (9,34).”
Li, T., Jia, L., Cao, Y., Chen, Q., & Li, C. (2018) · Genome biology · doi:10.1186/s13059-018-1430-4 · Cited by 71
“We used the rose software to identify enhancers [29].”
BackgroundMethodInfluentialEnhancers and chromatin structures: regulatory hubs in gene expression and diseases
Hu, Z., & Tee, W. (2017) · Bioscience Reports · doi:10.1042/bsr20160183 · Cited by 80
Mammalian Transcription Factor Networks: Recent Advances in Interrogating Biological Complexity
Wilkinson, A. C., Nakauchi, H., & Göttgens, B. (2017) · Cell Systems · doi:10.1016/j.cels.2017.07.004 · Cited by 76
CDK6 Antagonizes p53-Induced Responses during Tumorigenesis
Bellutti, F., Tigan, A.-S., Nebenfuehr, S., Dolezal, M., Zojer, M., Grausenburger, R., Hartenberger, S., Kollmann, S., Doma, E., Prchal‐Murphy, M., et al. (2018) · Cancer Discovery · doi:10.1158/2159-8290.cd-17-0912 · Cited by 75
“The finding that CDK6 is controlled by a superenhancer in glioblastoma, multiple myeloma, T-ALL, and colorectal cancer suggests that the level of CDK6 may be a predictive factor in several disease entities (41).”
BackgroundLu, J., Qian, J., Xu, Z., Yin, S., Zhou, L., Zheng, S., & Zhang, W. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.631486 · Cited by 77
BET Proteins as Attractive Targets for Cancer Therapeutics
Sarnik, J., Popławski, T., & Tokarz, P. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms222011102 · Cited by 78
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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