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• W2004966039 abstract "•Catalog of super-enhancers in 86 human cell and tissue types•Disease-associated sequence variation is enriched in super-enhancers•Cancer cells generate super-enhancers at key tumor pathogenesis genes•Super-enhancers provide biomarkers for disease diagnosis and therapy 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. 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. Transcription factors bind DNA regulatory elements called enhancers, which play key roles in the control of cell-type-specific gene expression programs (Bulger and Groudine, 2011Bulger M. Groudine M. Functional and mechanistic diversity of distal transcription enhancers.Cell. 2011; 144: 327-339Abstract Full Text Full Text PDF PubMed Scopus (189) Google Scholar, Calo and Wysocka, 2013Calo E. Wysocka J. Modification of enhancer chromatin: what, how, and why?.Mol. Cell. 2013; 49: 825-837Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar, Carey, 1998Carey M. The enhanceosome and transcriptional synergy.Cell. 1998; 92: 5-8Abstract Full Text Full Text PDF PubMed Scopus (384) Google Scholar, Lelli et al., 2012Lelli K.M. Slattery M. Mann R.S. Disentangling the many layers of eukaryotic transcriptional regulation.Annu. Rev. Genet. 2012; 46: 43-68Crossref PubMed Scopus (26) Google Scholar, Levine and Tjian, 2003Levine M. Tjian R. Transcription regulation and animal diversity.Nature. 2003; 424: 147-151Crossref PubMed Scopus (656) Google Scholar, Maston et al., 2006Maston G.A. Evans S.K. Green M.R. Transcriptional regulatory elements in the human genome.Annu. Rev. Genomics Hum. Genet. 2006; 7: 29-59Crossref PubMed Scopus (233) Google Scholar, Ong and Corces, 2011Ong C.T. Corces V.G. Enhancer function: new insights into the regulation of tissue-specific gene expression.Nat. Rev. Genet. 2011; 12: 283-293Crossref PubMed Scopus (171) Google Scholar, Panne, 2008Panne D. The enhanceosome.Curr. Opin. Struct. Biol. 2008; 18: 236-242Crossref PubMed Scopus (96) Google Scholar, Spitz and Furlong, 2012Spitz F. Furlong E.E. Transcription factors: from enhancer binding to developmental control.Nat. Rev. Genet. 2012; 13: 613-626Crossref PubMed Scopus (131) Google Scholar, Xie and Ren, 2013Xie W. Ren B. Developmental biology. Enhancing pluripotency and lineage specification.Science. 2013; 341: 245-247Crossref PubMed Scopus (5) Google Scholar). A typical mammalian cell contains thousands of active enhancers, and it has been estimated that there may be ∼1 million enhancers active in all human cells (Bernstein et al., 2012Bernstein B.E. Birney E. Dunham I. Green E.D. Gunter C. Snyder M. Epstein C.B. Frietze S. Harrow J. Kaul R. et al.ENCODE Project ConsortiumAn integrated encyclopedia of DNA elements in the human genome.Nature. 2012; 489: 57-74Crossref PubMed Scopus (1457) Google Scholar, Heintzman et al., 2009Heintzman N.D. Hon G.C. Hawkins R.D. Kheradpour P. Stark A. Harp L.F. Ye Z. Lee L.K. Stuart R.K. Ching C.W. et al.Histone modifications at human enhancers reflect global cell-type-specific gene expression.Nature. 2009; 459: 108-112Crossref PubMed Scopus (738) Google Scholar, Thurman et al., 2012Thurman R.E. Rynes E. Humbert R. Vierstra J. Maurano M.T. Haugen E. Sheffield N.C. Stergachis A.B. Wang H. Vernot B. et al.The accessible chromatin landscape of the human genome.Nature. 2012; 489: 75-82Crossref PubMed Scopus (336) Google Scholar). It is important to further understand enhancers and their components because they control specific gene expression programs, and much disease-associated sequence variation occurs in these regulatory elements (Grossman et al., 2013Grossman S.R. Andersen K.G. Shlyakhter I. Tabrizi S. Winnicki S. Yen A. Park D.J. Griesemer D. Karlsson E.K. Wong S.H. et al.1000 Genomes ProjectIdentifying recent adaptations in large-scale genomic data.Cell. 2013; 152: 703-713Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar, Hindorff et al., 2009Hindorff L.A. Sethupathy P. Junkins H.A. Ramos E.M. Mehta J.P. Collins F.S. Manolio T.A. Potential etiologic and functional implications of genome-wide association loci for human diseases and traits.Proc. Natl. Acad. Sci. USA. 2009; 106: 9362-9367Crossref PubMed Scopus (1477) Google Scholar, Lee and Young, 2013Lee T.I. Young R.A. Transcriptional regulation and its misregulation in disease.Cell. 2013; 152: 1237-1251Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar, Maurano et al., 2012Maurano M.T. Humbert R. Rynes E. Thurman R.E. Haugen E. Wang H. Reynolds A.P. Sandstrom R. Qu H. Brody J. et al.Systematic localization of common disease-associated variation in regulatory DNA.Science. 2012; 337: 1190-1195Crossref PubMed Scopus (276) Google Scholar). The set of enhancers that control any one cell’s gene expression program is probably best defined in murine embryonic stem cells (ESCs). Co-occupancy of murine ESC genomic sites by the master transcription factors Oct4, Sox2, and Nanog is highly predictive of enhancer activity (Chen et al., 2008Chen X. Xu H. Yuan P. Fang F. Huss M. Vega V.B. Wong E. Orlov Y.L. Zhang W. Jiang J. et al.Integration of external signaling pathways with the core transcriptional network in embryonic stem cells.Cell. 2008; 133: 1106-1117Abstract Full Text Full Text PDF PubMed Scopus (992) Google Scholar), and 8,794 enhancers have been identified in ESCs by using ChIP-seq data sets for Oct4, Sox2, and Nanog (Whyte et al., 2013Whyte W.A. Orlando D.A. Hnisz D. Abraham B.J. Lin C.Y. Kagey M.H. Rahl P.B. Lee T.I. Young R.A. Master transcription factors and mediator establish super-enhancers at key cell identity genes.Cell. 2013; 153: 307-319Abstract Full Text Full Text PDF PubMed Scopus (124) Google Scholar). A subset of these enhancers forms 231 unusual enhancer domains at most genes that control the pluripotent state; these super-enhancers consist of clusters of enhancers that are densely occupied by five key ESC transcription factors and the Mediator coactivator (Whyte et al., 2013Whyte W.A. Orlando D.A. Hnisz D. Abraham B.J. Lin C.Y. Kagey M.H. Rahl P.B. Lee T.I. Young R.A. Master transcription factors and mediator establish super-enhancers at key cell identity genes.Cell. 2013; 153: 307-319Abstract Full Text Full Text PDF PubMed Scopus (124) Google Scholar). There are many additional transcription factors, cofactors, and chromatin regulators that contribute to the control of ESCs (Ng and Surani, 2011Ng H.H. Surani M.A. The transcriptional and signalling networks of pluripotency.Nat. Cell Biol. 2011; 13: 490-496Crossref PubMed Scopus (94) Google Scholar, Orkin and Hochedlinger, 2011Orkin S.H. Hochedlinger K. Chromatin connections to pluripotency and cellular reprogramming.Cell. 2011; 145: 835-850Abstract Full Text Full Text PDF PubMed Scopus (119) Google Scholar, Young, 2011Young R.A. Control of the embryonic stem cell state.Cell. 2011; 144: 940-954Abstract Full Text Full Text PDF PubMed Scopus (272) Google Scholar), and it would be instructive to know how these occupy enhancers and super-enhancers in ESCs. Similarly, it would be useful to know if super-enhancers are transcribed, as enhancer RNAs (eRNAs) have been proposed to contribute to enhancer activity (Lai et al., 2013Lai F. Orom U.A. Cesaroni M. Beringer M. Taatjes D.J. Blobel G.A. Shiekhattar R. Activating RNAs associate with Mediator to enhance chromatin architecture and transcription.Nature. 2013; 494: 497-501Crossref PubMed Scopus (93) Google Scholar, Lam et al., 2013Lam M.T. Cho H. Lesch H.P. Gosselin D. Heinz S. Tanaka-Oishi Y. Benner C. Kaikkonen M.U. Kim A.S. Kosaka M. et al.Rev-Erbs repress macrophage gene expression by inhibiting enhancer-directed transcription.Nature. 2013; 498: 511-515Crossref PubMed Scopus (70) Google Scholar, Li et al., 2013Li W. Notani D. Ma Q. Tanasa B. Nunez E. Chen A.Y. Merkurjev D. Zhang J. Ohgi K. Song X. et al.Functional roles of enhancer RNAs for oestrogen-dependent transcriptional activation.Nature. 2013; 498: 516-520Crossref PubMed Scopus (85) Google Scholar, Ling et al., 2004Ling J. Ainol L. Zhang L. Yu X. Pi W. Tuan D. HS2 enhancer function is blocked by a transcriptional terminator inserted between the enhancer and the promoter.J. Biol. Chem. 2004; 279: 51704-51713Crossref PubMed Scopus (41) Google Scholar, Mousavi et al., 2013Mousavi K. Zare H. Dell’orso S. Grontved L. Gutierrez-Cruz G. Derfoul A. Hager G.L. Sartorelli V. eRNAs Promote Transcription by Establishing Chromatin Accessibility at Defined Genomic Loci.Mol. Cell. 2013; 51: 606-617Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar, Ørom et al., 2010Ørom U.A. Derrien T. Beringer M. Gumireddy K. Gardini A. Bussotti G. Lai F. Zytnicki M. Notredame C. Huang Q. et al.Long noncoding RNAs with enhancer-like function in human cells.Cell. 2010; 143: 46-58Abstract Full Text Full Text PDF PubMed Scopus (427) Google Scholar). Super-enhancers are associated with key genes that control cell state in cells where they have been identified thus far, so identification of these domains in additional cell types could provide a valuable resource for further study of cellular control. We have generated a catalog of super-enhancers in 86 human cell and tissue types. These super-enhancers are associated with genes encoding cell-type-specific transcription factors and thus identify candidate master transcription factors for many cell types that should prove useful for further understanding transcriptional control of cell state and for reprogramming studies. Using this catalog, we find that DNA sequence variation associated with specific diseases is especially enriched in the super-enhancers of disease-relevant cells, suggesting that hypotheses regarding the role of specific cell types and genes in many diseases might be guided by knowledge of super-enhancers. Furthermore, tumor cells acquire super-enhancers at key oncogenes and at genes that function in the acquisition of hallmark capabilities in cancer, suggesting that these domains provide biomarkers for tumor-specific pathologies that may be valuable for diagnosis and therapeutic intervention. We discuss the implications of these observations for future study of disease. Super-enhancers are clusters of enhancers—formed by binding of high levels of master transcription factors and Mediator coactivator—that drive high-level expression of genes encoding key regulators of cell identity (Figure 1A) (Whyte et al., 2013Whyte W.A. Orlando D.A. Hnisz D. Abraham B.J. Lin C.Y. Kagey M.H. Rahl P.B. Lee T.I. Young R.A. Master transcription factors and mediator establish super-enhancers at key cell identity genes.Cell. 2013; 153: 307-319Abstract Full Text Full Text PDF PubMed Scopus (124) Google Scholar). Five ESC transcription factors were previously shown to occupy super-enhancers (Oct4, Sox2, Nanog, Klf4, and Esrrb) (Whyte et al., 2013Whyte W.A. Orlando D.A. Hnisz D. Abraham B.J. Lin C.Y. Kagey M.H. Rahl P.B. Lee T.I. Young R.A. Master transcription factors and mediator establish super-enhancers at key cell identity genes.Cell. 2013; 153: 307-319Abstract Full Text Full Text PDF PubMed Scopus (124) Google Scholar), but there are many additional transcription factors that contribute to the control of ESCs (Ng and Surani, 2011Ng H.H. Surani M.A. The transcriptional and signalling networks of pluripotency.Nat. Cell Biol. 2011; 13: 490-496Crossref PubMed Scopus (94) Google Scholar, Orkin and Hochedlinger, 2011Orkin S.H. Hochedlinger K. Chromatin connections to pluripotency and cellular reprogramming.Cell. 2011; 145: 835-850Abstract Full Text Full Text PDF PubMed Scopus (119) Google Scholar, Young, 2011Young R.A. Control of the embryonic stem cell state.Cell. 2011; 144: 940-954Abstract Full Text Full Text PDF PubMed Scopus (272) Google Scholar). We compiled ChIP-seq data for 15 additional transcription factors in ESCs, for which high-quality ChIP-seq data were available, and investigated whether they occupy enhancers defined by Oct4, Sox2, and Nanog (OSN) co-occupancy (Whyte et al., 2013Whyte W.A. Orlando D.A. Hnisz D. Abraham B.J. Lin C.Y. Kagey M.H. Rahl P.B. Lee T.I. Young R.A. Master transcription factors and mediator establish super-enhancers at key cell identity genes.Cell. 2013; 153: 307-319Abstract Full Text Full Text PDF PubMed Scopus (124) Google Scholar) (Table S1 available online). The analysis showed that six additional transcription factors (Nr5a2, Prdm14, Tcfcp2l1, Smad3, Stat3, and Tcf3) occupy both typical enhancers and super-enhancers and that all of these are enriched in super-enhancers (Figures 1B–1E). Each of these factors has previously been shown to play important roles in ESC biology (Ng and Surani, 2011Ng H.H. Surani M.A. The transcriptional and signalling networks of pluripotency.Nat. Cell Biol. 2011; 13: 490-496Crossref PubMed Scopus (94) Google Scholar, Orkin and Hochedlinger, 2011Orkin S.H. Hochedlinger K. Chromatin connections to pluripotency and cellular reprogramming.Cell. 2011; 145: 835-850Abstract Full Text Full Text PDF PubMed Scopus (119) Google Scholar, Young, 2011Young R.A. Control of the embryonic stem cell state.Cell. 2011; 144: 940-954Abstract Full Text Full Text PDF PubMed Scopus (272) Google Scholar). In contrast, nine other transcription factors (c-Myc, CTCF, Zfx, Tbx3, YY1, Tfe3, Kap1/Zfp57, Smad1, and Ronin) were not similarly enriched in enhancers (Table S1) and instead occupied other regions of the genome such as promoter-proximal sites or sites that border topological domains (Figure S1A). It is particularly interesting that Smad3, Stat3, and Tcf3 are enriched in super-enhancer domains because these are transcription factor targets of the TGF-β-, LIF-, and Wnt-signaling pathways, respectively. Previous studies have shown that these transcription factors are recruited to enhancers formed by master transcription factors (Chen et al., 2008Chen X. Xu H. Yuan P. Fang F. Huss M. Vega V.B. Wong E. Orlov Y.L. Zhang W. Jiang J. et al.Integration of external signaling pathways with the core transcriptional network in embryonic stem cells.Cell. 2008; 133: 1106-1117Abstract Full Text Full Text PDF PubMed Scopus (992) Google Scholar, Mullen et al., 2011Mullen A.C. Orlando D.A. Newman J.J. Lovén J. Kumar R.M. Bilodeau S. Reddy J. Guenther M.G. DeKoter R.P. Young R.A. Master transcription factors determine cell-type-specific responses to TGF-β signaling.Cell. 2011; 147: 565-576Abstract Full Text Full Text PDF PubMed Scopus (131) Google Scholar), and evidence for enrichment of these factors at super-enhancers shows how these signaling pathways can converge on key genes that control ESC identity.Figure S1Genomic Localization and Features of Transcription Factors in mESCs, Related to Figure 1Show full caption(A) Metagene representations of mean ChIP-seq density in regions surrounding constituents of super-enhancers and typical enhancers, active promoters, and the borders of topological domains for the indicated transcription factors in mESCs. For each transcription factor, the leftmost panel shows background-subtracted densities within size-normalized constituents of super-enhancers (red) and typical enhancers (gray) plus adjacent 2.5kb regions. The center panel shows background-subtracted densities within 1kb of RefSeq-defined transcription start sites of active transcripts. Active transcripts were defined as having an RNA Polymerase II mean ChIP-seq signal > 1 rpm/bp in this region. The right panel shows background-subtracted densities within ± 500kb of borders of topological domains in mESC as defined in (Dixon et al., 2012Dixon J.R. Selvaraj S. Yue F. Kim A. Li Y. Shen Y. Hu M. Liu J.S. Ren B. Topological domains in mammalian genomes identified by analysis of chromatin interactions.Nature. 2012; 485: 376-380Crossref PubMed Scopus (372) Google Scholar).(B) (Top) Table depicting transcription factor binding motifs at constituent enhancers within typical enhancer regions, and associated p values. P values for motifs within typical enhancers arise by comparison of 1,573 typical enhancer constituents to genomic background (see Extended Experimental Procedures). Many typical enhancer p values thus appear more significant than their counterparts at super-enhancers (Figure 1F), but the p values are not directly comparable due to the difference in sample size between the two classes of enhancers.(C) Comparison of motif frequency per constituent of super-enhancers and typical enhancers shows that super-enhancer constituents are enriched in motif occurrences for these factors compared to typical enhancer constituents (t test, p < 10−15). Box plot whiskers extend to 1.5x the interquartile range.View Large Image Figure ViewerDownload Hi-res image Download (PPT) (A) Metagene representations of mean ChIP-seq density in regions surrounding constituents of super-enhancers and typical enhancers, active promoters, and the borders of topological domains for the indicated transcription factors in mESCs. For each transcription factor, the leftmost panel shows background-subtracted densities within size-normalized constituents of super-enhancers (red) and typical enhancers (gray) plus adjacent 2.5kb regions. The center panel shows background-subtracted densities within 1kb of RefSeq-defined transcription start sites of active transcripts. Active transcripts were defined as having an RNA Polymerase II mean ChIP-seq signal > 1 rpm/bp in this region. The right panel shows background-subtracted densities within ± 500kb of borders of topological domains in mESC as defined in (Dixon et al., 2012Dixon J.R. Selvaraj S. Yue F. Kim A. Li Y. Shen Y. Hu M. Liu J.S. Ren B. Topological domains in mammalian genomes identified by analysis of chromatin interactions.Nature. 2012; 485: 376-380Crossref PubMed Scopus (372) Google Scholar). (B) (Top) Table depicting transcription factor binding motifs at constituent enhancers within typical enhancer regions, and associated p values. P values for motifs within typical enhancers arise by comparison of 1,573 typical enhancer constituents to genomic background (see Extended Experimental Procedures). Many typical enhancer p values thus appear more significant than their counterparts at super-enhancers (Figure 1F), but the p values are not directly comparable due to the difference in sample size between the two classes of enhancers. (C) Comparison of motif frequency per constituent of super-enhancers and typical enhancers shows that super-enhancer constituents are enriched in motif occurrences for these factors compared to typical enhancer constituents (t test, p < 10−15). Box plot whiskers extend to 1.5x the interquartile range. To assess whether the 11 transcription factors that are enriched at super-enhancers contribute to super-enhancer formation by binding to known DNA sequence motifs, we analyzed the frequency of these binding motifs at super-enhancer regions. For all nine transcription factors for which binding motifs are available, we found that the cognate motif showed significant enrichment at super-enhancer constituents relative to background expectation, and super-enhancers were enriched for these motifs compared to typical enhancers (Figures 1F, S1B, and S1C). These results suggest that the nine transcription factors contribute to super-enhancers by binding directly to their known DNA sequence motifs. Previous studies have described a model of core transcriptional regulatory circuitry that includes Oct4, Sox2, and Nanog (Boyer et al., 2005Boyer 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.Core transcriptional regulatory circuitry in human embryonic stem cells.Cell. 2005; 122: 947-956Abstract Full Text Full Text PDF PubMed Scopus (2013) Google Scholar). The evidence that these and additional ESC transcription factors form super-enhancers that drive genes that are essential for control of cell identity suggests a revised model of transcriptional regulatory circuitry for ESCs (Figure 1G). This model contains an interconnected autoregulatory loop like that originally proposed for Oct4, Sox2, and Nanog (Boyer et al., 2005Boyer 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.Core transcriptional regulatory circuitry in human embryonic stem cells.Cell. 2005; 122: 947-956Abstract Full Text Full Text PDF PubMed Scopus (2013) Google Scholar) but consists of the additional ESC transcription factors that meet three criteria: (1) their genes are driven by super-enhancers, (2) they co-occupy their own super-enhancers as well as those of the other master genes, and (3) they play important roles in regulation of ESC state and iPSC reprogramming. Super-enhancers are occupied by unusually high levels of the Mediator coactivator (Whyte et al., 2013Whyte W.A. Orlando D.A. Hnisz D. Abraham B.J. Lin C.Y. Kagey M.H. Rahl P.B. Lee T.I. Young R.A. Master transcription factors and mediator establish super-enhancers at key cell identity genes.Cell. 2013; 153: 307-319Abstract Full Text Full Text PDF PubMed Scopus (124) Google Scholar). Previous studies have described the activities of RNA polymerase II and various cofactors, chromatin regulators, and RNA at specific enhancers (Calo and Wysocka, 2013Calo E. Wysocka J. Modification of enhancer chromatin: what, how, and why?.Mol. Cell. 2013; 49: 825-837Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar, Kagey et al., 2010Kagey M.H. Newman J.J. Bilodeau S. Zhan Y. Orlando D.A. van Berkum N.L. Ebmeier C.C. Goossens J. Rahl P.B. Levine S.S. et al.Mediator and cohesin connect gene expression and chromatin architecture.Nature. 2010; 467: 430-435Crossref PubMed Scopus (458) Google Scholar, Lai et al., 2013Lai F. Orom U.A. Cesaroni M. Beringer M. Taatjes D.J. Blobel G.A. Shiekhattar R. Activating RNAs associate with Mediator to enhance chromatin architecture and transcription.Nature. 2013; 494: 497-501Crossref PubMed Scopus (93) Google Scholar, Lam et al., 2013Lam M.T. Cho H. Lesch H.P. Gosselin D. Heinz S. Tanaka-Oishi Y. Benner C. Kaikkonen M.U. Kim A.S. Kosaka M. et al.Rev-Erbs repress macrophage gene expression by inhibiting enhancer-directed transcription.Nature. 2013; 498: 511-515Crossref PubMed Scopus (70) Google Scholar, Li et al., 2013Li W. Notani D. Ma Q. Tanasa B. Nunez E. Chen A.Y. Merkurjev D. Zhang J. Ohgi K. Song X. et al.Functional roles of enhancer RNAs for oestrogen-dependent transcriptional activation.Nature. 2013; 498: 516-520Crossref PubMed Scopus (85) Google Scholar, Ling et al., 2004Ling J. Ainol L. Zhang L. Yu X. Pi W. Tuan D. HS2 enhancer function is blocked by a transcriptional terminator inserted between the enhancer and the promoter.J. Biol. Chem. 2004; 279: 51704-51713Crossref PubMed Scopus (41) Google Scholar, Mousavi et al., 2013Mousavi K. Zare H. Dell’orso S. Grontved L. Gutierrez-Cruz G. Derfoul A. Hager G.L. Sartorelli V. eRNAs Promote Transcription by Establishing Chromatin Accessibility at Defined Genomic Loci.Mol. Cell. 2013; 51: 606-617Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar, Natoli and Andrau, 2012Natoli G. Andrau J.C. Noncoding transcription at enhancers: general principles and functional models.Annu. Rev. Genet. 2012; 46: 1-19Crossref PubMed Scopus (49) Google Scholar, Ong and Corces, 2011Ong C.T. Corces V.G. Enhancer function: new insights into the regulation of tissue-specific gene expression.Nat. Rev. Genet. 2011; 12: 283-293Crossref PubMed Scopus (171) Google Scholar, Ørom et al., 2010Ørom U.A. Derrien T. Beringer M. Gumireddy K. Gardini A. Bussotti G. Lai F. Zytnicki M. Notredame C. Huang Q. et al.Long noncoding RNAs with enhancer-like function in human cells.Cell. 2010; 143: 46-58Abstract Full Text Full Text PDF PubMed Scopus (427) Google Scholar), so we used published and newly generated ChIP-seq and RNA-seq data to investigate how these components are associated with enhancers and super-enhancers across the ESC genome. The results indicate that RNA polymerase II, Mediator, cohesin, Nipbl, p300, CBP, Chd7, Brd4, and components of the esBAF (Brg1) and Lsd1-NuRD complexes are all enriched in super-enhancers relative to typical enhancers (Figures 2A–2E and Table S1). RNA polymerase II can transcribe enhancers, producing noncoding RNAs that in some cases contribute to enhancer activity (Kim et al., 2010Kim T.K. Hemberg M. Gray J.M. Costa A.M. Bear D.M. Wu J. Harmin D.A. Laptewicz M. Barbara-Haley K. Kuersten S. et al.Widespread transcription at neuronal activity-regulated enhancers.Nature. 2010; 465: 182-187Crossref PubMed Scopus (509) Google Scholar, Lam et al., 2013Lam M.T. Cho H. Lesch H.P. Gosselin D. Heinz S. Tanaka-Oishi Y. Benner C. Kaikkonen M.U. Kim A.S. Kosaka M. et al.Rev-Erbs repress macrophage gene expression by inhibiting enhancer-directed transcription.Nature. 2013; 498: 511-515Crossref PubMed Scopus (70) Google Scholar, Li et al., 2013Li W. Notani D. Ma Q. Tanasa B. Nunez E. Chen A.Y. Merkurjev D. Zhang J. Ohgi K. Song X. et al.Functional roles of enhancer RNAs for oestrogen-dependent transcriptional activation.Nature. 2013; 498: 516-520Crossref PubMed Scopus (85) Google Scholar, Natoli and Andrau, 2012Natoli G. Andrau J.C. Noncoding transcription at enhancers: general principles and functional models.Annu. Rev. Genet. 2012; 46: 1-19Crossref PubMed Scopus (49) Google Scholar, Sigova et al., 2013Sigova A.A. Mullen A.C. Molinie B. Gupta S. Orlando D.A. Guenther M.G. Almada A.E. Lin C. Sharp P.A. Giallourakis C.C. Young R.A. Divergent transcription of long noncoding RNA/mRNA gene pairs in embryonic stem cells.Proc. Natl. Acad. Sci. USA. 2013; 110: 2876-2881Crossref PubMed Scopus (53) Google Scholar); we found that RNA polymerase II and RNA were highly enriched at super-enhancers relative to typical enhancers (Figure 2C). It was notable that a broad spectrum of cofactors and chromatin regulators that are responsible for gene activation, enhancer looping, histone modification, and nucleosome remodeling are especially enriched in ESC super-enhancers. The Mediator coactivator binds Nipbl, which loads cohesin, thus facilitating looping of enhancers to the promoters of their target genes (Kagey et al., 2010Kagey M.H. Newman J.J. Bilodeau S. Zhan Y. Orlando D.A. van Berkum N.L. Ebmeier C.C. Goossens J. Rahl P.B. Levine S.S. et al.Mediator and cohesin connect gene expression and chromatin architecture.Nature. 2010; 467: 430-435Crossref PubMed Scopus (458) Google Scholar). The coactivator p300 is a histone acetyltransferase, which is generally found at enhancer regions (Heintzman et al., 2007Heintzman N.D. Stuart R.K. Hon G. Fu Y. Ching C.W. Hawkins R.D. Barrera L.O. Van Calcar S. Qu C. Ching K.A. et al.Distinct and predictive chromatin signatures of transcriptional promoters and enhancers in the human genome.Nat. Genet. 2007; 39: 311-318Crossref PubMed Scopus (1034) Google Scholar, Visel et al., 2009Visel A. Blow M.J. Li Z. Zhang T. Akiyama J.A. Holt A. Plajzer-Frick I. Shoukry M. Wright C. Chen F. et al.ChIP-seq accurately predicts tissue-specific activity of enhancers.Nature. 2009; 457: 854-858Crossref PubMed Scopus (587) Google Scholar). CBP is a transcriptional coactivator that interacts with p300 and promotes synergy between enhancer components (Merika et al., 1998Merika M. Williams A.J. Chen G. Collins T. Thanos D. Recruitment of CBP/p300 by the IFN beta enhanceosome is required for synergistic activation of transcription.Mol. Cell. 1998; 1: 277-287Abstract Full Text Full Text PDF PubMed Google Scholar). Chd7 is a chromatin remodeler that also interacts with p300 and is often found at enhancers (Schnetz et al., 2010Schnetz M.P. Handoko L. Akhtar-Zaidi B. Bartels C.F. Pereira C.F. Fisher A.G. Adams D.J. Flicek P. Crawford G.E. Laframboise" @default.
• W2004966039 created "2016-06-24" @default.
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• W2004966039 date "2013-11-01" @default.
• W2004966039 modified "2023-10-13" @default.
• W2004966039 title "Super-Enhancers in the Control of Cell Identity and Disease" @default.
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