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In genetics, a super-enhancer is a region of the mammalian genome comprising multiple enhancers that is collectively bound by an array of transcription factor proteins to drive transcription of genes involved in cell identity.^[1]^[2]^[3] Because super-enhancers are frequently identified near genes important for controlling and defining cell identity, they may thus be used to quickly identify key nodes regulating cell identity. ^[3]^[4]

Enhancers have several quantifiable traits that have a range of values, and these traits are generally elevated at super-enhancers. Super-enhancers are bound by higher levels of transcription-regulating proteins and are associated with genes that are more highly expressed. ^[1]^[5]^[6]^[7] Expression of genes associated with super-enhancers is particularly sensitive to perturbations, which may facilitate cell state transitions or explain sensitivity of super-enhancer—associated genes to small molecules that target transcription. ^[1]^[5]^[6]^[8]^[9]

History

The regulation of transcription by enhancers has been studied since the 1980s. ^[10]^[11]^[12]^[13]^[14] Large or multi-component transcription regulators with a range of mechanistic properties, including locus control regions, clustered open regulatory elements, and transcription initiation platforms, were observed shortly thereafter. ^[15]^[16]^[17]^[18] More recent research has suggested that these different categories of regulatory elements may represent subtypes of super-enhancer. ^[3]^[19]

In 2013, two labs identified large enhancers near several genes especially important for establishing cell identities. While Richard A. Young and colleagues identified super-enhancers, Francis Collins and colleagues identified stretch enhancers. ^[1]^[2] Both super-enhancers and stretch enhancers are clusters of enhancers that control cell-specific genes and may be largely synonymous. ^[2]^[20]

As currently defined, the term “super-enhancer” was introduced by Young’s lab to describe regions identified in mouse embryonic stem cells (ESCs). ^[1] These particularly large, potent enhancer regions were found to control the genes that establish the embryonic stem cell identity, including Oct-4, Sox2, Nanog, Klf4, and Esrrb. Perturbation of the super-enhancers associated with these genes showed a range of effects on their target genes’ expression. ^[20] Super-enhancers have been since identified near cell identity-regulators in a range of mouse and human tissues. ^[2]^[3]^[21]^[22]^[23]^[24]^[25]^[26]^[27]^[28]^[29]^[30]^[31]^[32]^[33]^[34]^[35]^[36]^[37]

Function

The enhancers comprising super-enhancers share the functions of enhancers, including binding transcription factor proteins, looping to target genes, and activating transcription. ^[1]^[3]^[19]^[20] Three notable traits of enhancers comprising super-enhancers are their clustering in genomic proximity, their exceptional signal of transcription-regulating proteins, and their high frequency of physical interaction with each other. Perturbing the DNA of enhancers comprising super-enhancers showed a range of effects on the expression of cell identity genes, suggesting a complex relationship between the constituent enhancers. ^[20]

High levels of many transcription factors and co-factors are seen at super-enhancers (e.g., CDK7, BRD4, and |Mediator). ^[1]^[3]^[5]^[6]^[8]^[9]^[19] This high concentration of transcription-regulating proteins suggests why their target genes tend to be more highly expressed than other classes of genes. However, housekeeping genes tend to be more highly expressed than super-enhancer—associated genes. ^[1]

Super-enhancers may have been evolved at key cell identity genes to render the transcription of these genes responsive to an array of external cues. ^[20] The enhancers comprising a super-enhancer can each be responsive to different signals, which allows the transcription of a single gene to be regulated by multiple signaling pathways. ^[20] Pathways seen to regulate their target genes using super-enhancers include Wnt, TGFb, LIF, BDNF, and NOTCH. ^[20]^[38]^[39]^[40]^[41] The constituent enhancers of super-enhancers physically interact with each other and their target genes. ^[7]^[22]^[42]

Relevance to Disease

Mutations in super-enhancers have been noted in various diseases, including cancers, type 1 diabetes, Alzheimer’s disease, lupus, rheumatoid arthritis, multiple sclerosis, systemic scleroderma, primary biliary cirrhosis, Crohn’s disease, Graves disease, vitiligo, and atrial fibrillation. ^[2]^[3]^[6]^[25]^[32]^[35]^[43]^[44]^[45]^[46]^[47] A similar enrichment in disease-associated sequence variation has also been observed for stretch enhancers. ^[2]

Super-enhancers may play important roles in the misregulation of gene expression in cancer. During tumor development, tumor cells acquire super-enhancers at key oncogenes, which drive higher levels of transcription of these genes than in healthy cells. ^[3]^[5]^[42]^[43]^[48]^[49]^[50]^[51]^[52]^[53]^[54]^[55]^[56]^[57] Acquired super-enhancers may thus be biomarkers that could be useful for diagnosis and therapeutic intervention. ^[20]

Proteins enriched at super-enhancers include the targets of small molecules that target transcription-regulating proteins and have been deployed against cancers. ^[5]^[6]^[25]^[58] For instance, super-enhancers rely on exceptional amounts of CDK7, and, in cancer, multiple papers report the loss of expression of their target genes when cells are treated with the CDK7 inhibitor THZ1.^[5]^[8]^[9]^[59] Similarly, super-enhancers are enriched in the target of the JQ1 small molecule, BRD4, so treatment with JQ1 causes exceptional losses in expression for super-enhancer—associated genes. ^[6]

Identification

Super-enhancers have been most commonly identified by locating genomic regions that are highly enriched in ChIP-Seq signal. ChIP-Seq experiments targeting master transcription factors and co-factors like Mediator or BRD4 have been used, but the most frequently used is H3K27ac-marked nucleosomes. ^[1]^[3]^[6]^[60]^[61]^[62] The program “ROSE” (Rank Ordering of Super-Enhancers) is commonly used to identify super-enhancers from ChIP-Seq data. This program stitches together previously identified enhancer regions and ranks these stitched enhancers by their ChIP-Seq signal. ^[1] The stitching distance selected to combine multiple individual enhancers into larger domains can vary. Because some markers of enhancer activity also are enriched in promoters, regions within promoters of genes can be disregarded. ROSE separates super-enhancers from typical enhancers by their exceptional enrichment in a mark of enhancer activity.

References

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[Wang2015-59] Wang, Y; Zhang, T; Kwiatkowski, N; Abraham, BJ; Lee, TI; Xie, S; Yuzugullu, H; Von, T; Li, H; Lin, Z; Stover, DG; Lim, E; Wang, ZC; Iglehart, JD; Young, RA; Gray, NS; Zhao, JJ (24 September 2015). "CDK7-dependent transcriptional addiction in triple-negative breast cancer". Cell. 163 (1): 174–86. PMID 26406377.

[Wei2016-60] Wei, Y; Zhang, S; Shang, S; Zhang, B; Li, S; Wang, X; Wang, F; Su, J; Wu, Q; Liu, H; Zhang, Y (4 January 2016). "SEA: a super-enhancer archive". Nucleic acids research. 44 (D1): D172-9. PMID 26578594.

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+In genetics, a super-enhancer is a region of the mammalian genome comprising multiple [[Enhancer (genetics)|enhancers]] that is collectively bound by an array of [[transcription factor]] proteins to drive [[Transcription (genetics)|transcription]] of genes involved in cell identity.<ref name="Whyte2013">{{cite journal|last1=Whyte|first1=WA|last2=Orlando|first2=DA|last3=Hnisz|first3=D|last4=Abraham|first4=BJ|last5=Lin|first5=CY|last6=Kagey|first6=MH|last7=Rahl|first7=PB|last8=Lee|first8=TI|last9=Young|first9=RA|title=Master transcription factors and mediator establish super-enhancers at key cell identity genes.|journal=Cell|date=11 April 2013|volume=153|issue=2|pages=307-19|pmid=23582322}}</ref><ref name="Parker2013">{{cite journal|last1=Parker|first1=SC|last2=Stitzel|first2=ML|last3=Taylor|first3=DL|last4=Orozco|first4=JM|last5=Erdos|first5=MR|last6=Akiyama|first6=JA|last7=van Bueren|first7=KL|last8=Chines|first8=PS|last9=Narisu|first9=N|last10=NISC Comparative Sequencing|first10=Program|last11=Black|first11=BL|last12=Visel|first12=A|last13=Pennacchio|first13=LA|last14=Collins|first14=FS|last15=National Institutes of Health Intramural Sequencing Center Comparative Sequencing Program|first15=Authors|last16=NISC Comparative Sequencing Program|first16=Authors|title=Chromatin stretch enhancer states drive cell-specific gene regulation and harbor human disease risk variants.|journal=Proceedings of the National Academy of Sciences of the United States of America|date=29 October 2013|volume=110|issue=44|pages=17921-6|pmid=24127591}}</ref><ref name="Hnisz2013">{{cite journal|last1=Hnisz|first1=D|last2=Abraham|first2=BJ|last3=Lee|first3=TI|last4=Lau|first4=A|last5=Saint-André|first5=V|last6=Sigova|first6=AA|last7=Hoke|first7=HA|last8=Young|first8=RA|title=Super-enhancers in the control of cell identity and disease.|journal=Cell|date=7 November 2013|volume=155|issue=4|pages=934-47|pmid=24119843}}</ref>  Because super-enhancers are frequently identified near genes important for controlling and defining cell identity, they may thus be used to quickly identify key nodes regulating cell identity. <ref name=Hnisz2013 /><ref name="Saint-André2016">{{cite journal|last1=Saint-André|first1=V|last2=Federation|first2=AJ|last3=Lin|first3=CY|last4=Abraham|first4=BJ|last5=Reddy|first5=J|last6=Lee|first6=TI|last7=Bradner|first7=JE|last8=Young|first8=RA|title=Models of human core transcriptional regulatory circuitries.|journal=Genome research|date=March 2016|volume=26|issue=3|pages=385-96|pmid=26843070}}</ref>
+Enhancers have several quantifiable traits that have a range of values, and these traits are generally elevated at super-enhancers. Super-enhancers are bound by higher levels of transcription-regulating proteins and are associated with genes that are more highly expressed. <ref name= Whyte2013/><ref name="Kwiatkowski2014">{{cite journal|last1=Kwiatkowski|first1=N|last2=Zhang|first2=T|last3=Rahl|first3=PB|last4=Abraham|first4=BJ|last5=Reddy|first5=J|last6=Ficarro|first6=SB|last7=Dastur|first7=A|last8=Amzallag|first8=A|last9=Ramaswamy|first9=S|last10=Tesar|first10=B|last11=Jenkins|first11=CE|last12=Hannett|first12=NM|last13=McMillin|first13=D|last14=Sanda|first14=T|last15=Sim|first15=T|last16=Kim|first16=ND|last17=Look|first17=T|last18=Mitsiades|first18=CS|last19=Weng|first19=AP|last20=Brown|first20=JR|last21=Benes|first21=CH|last22=Marto|first22=JA|last23=Young|first23=RA|last24=Gray|first24=NS|title=Targeting transcription regulation in cancer with a covalent CDK7 inhibitor.|journal=Nature|date=31 July 2014|volume=511|issue=7511|pages=616-20|pmid=25043025}}</ref><ref name="Lovén2013">{{cite journal|last1=Lovén|first1=J|last2=Hoke|first2=HA|last3=Lin|first3=CY|last4=Lau|first4=A|last5=Orlando|first5=DA|last6=Vakoc|first6=CR|last7=Bradner|first7=JE|last8=Lee|first8=TI|last9=Young|first9=RA|title=Selective inhibition of tumor oncogenes by disruption of super-enhancers.|journal=Cell|date=11 April 2013|volume=153|issue=2|pages=320-34|pmid=23582323}}</ref><ref name="Dowen2014">{{cite journal|last1=Dowen|first1=JM|last2=Fan|first2=ZP|last3=Hnisz|first3=D|last4=Ren|first4=G|last5=Abraham|first5=BJ|last6=Zhang|first6=LN|last7=Weintraub|first7=AS|last8=Schuijers|first8=J|last9=Lee|first9=TI|last10=Zhao|first10=K|last11=Young|first11=RA|title=Control of cell identity genes occurs in insulated neighborhoods in mammalian chromosomes.|journal=Cell|date=9 October 2014|volume=159|issue=2|pages=374-87|pmid=25303531}}</ref> Expression of genes associated with super-enhancers is particularly sensitive to perturbations, which may facilitate cell state transitions or explain sensitivity of super-enhancer—associated genes to small molecules that target transcription. <ref name= Whyte2013/><ref name= Kwiatkowski2014 /><ref name= Lovén2013 /><ref name="Christensen2014">{{cite journal|last1=Christensen|first1=CL|last2=Kwiatkowski|first2=N|last3=Abraham|first3=BJ|last4=Carretero|first4=J|last5=Al-Shahrour|first5=F|last6=Zhang|first6=T|last7=Chipumuro|first7=E|last8=Herter-Sprie|first8=GS|last9=Akbay|first9=EA|last10=Altabef|first10=A|last11=Zhang|first11=J|last12=Shimamura|first12=T|last13=Capelletti|first13=M|last14=Reibel|first14=JB|last15=Cavanaugh|first15=JD|last16=Gao|first16=P|last17=Liu|first17=Y|last18=Michaelsen|first18=SR|last19=Poulsen|first19=HS|last20=Aref|first20=AR|last21=Barbie|first21=DA|last22=Bradner|first22=JE|last23=George|first23=RE|last24=Gray|first24=NS|last25=Young|first25=RA|last26=Wong|first26=KK|title=Targeting transcriptional addictions in small cell lung cancer with a covalent CDK7 inhibitor.|journal=Cancer cell|date=8 December 2014|volume=26|issue=6|pages=909-22|pmid=25490451}}</ref><ref name="Chipumuro2014">{{cite journal|last1=Chipumuro|first1=E|last2=Marco|first2=E|last3=Christensen|first3=CL|last4=Kwiatkowski|first4=N|last5=Zhang|first5=T|last6=Hatheway|first6=CM|last7=Abraham|first7=BJ|last8=Sharma|first8=B|last9=Yeung|first9=C|last10=Altabef|first10=A|last11=Perez-Atayde|first11=A|last12=Wong|first12=KK|last13=Yuan|first13=GC|last14=Gray|first14=NS|last15=Young|first15=RA|last16=George|first16=RE|title=CDK7 inhibition suppresses super-enhancer-linked oncogenic transcription in MYCN-driven cancer.|journal=Cell|date=20 November 2014|volume=159|issue=5|pages=1126-39|pmid=25416950}}</ref>
 ==History==
-The [[transcriptional regulation|regulation of transcription]] by [[enhancer (genetics)|enhancers]] has been studied since the 1980s. <ref>{{cite journal|last1=Banerji|first1=J|last2=Rusconi|first2=S|last3=Schaffner|first3=W|title=Expression of a beta-globin gene is enhanced by remote SV40 DNA sequences.|journal=Cell|date=December 1981|volume=27|issue=2 Pt 1|pages=299-308|pmid=6277502}}</ref><ref>{{cite journal|last1=Benoist|first1=C|last2=Chambon|first2=P|title=In vivo sequence requirements of the SV40 early promotor region.|journal=Nature|date=26 March 1981|volume=290|issue=5804|pages=304-10|pmid=6259538}}</ref><ref>{{cite journal|last1=Gruss|first1=P|last2=Dhar|first2=R|last3=Khoury|first3=G|title=Simian virus 40 tandem repeated sequences as an element of the early promoter.|journal=Proceedings of the National Academy of Sciences of the United States of America|date=February 1981|volume=78|issue=2|pages=943-7|pmid=6262784}}</ref><ref>{{cite journal|last1=Evans|first1=T|last2=Felsenfeld|first2=G|last3=Reitman|first3=M|title=Control of globin gene transcription.|journal=Annual review of cell biology|date=1990|volume=6|pages=95-124|pmid=2275826}}</ref><ref>{{cite journal|last1=Cellier|first1=M|last2=Belouchi|first2=A|last3=Gros|first3=P|title=Resistance to intracellular infections: comparative genomic analysis of Nramp.|journal=Trends in genetics : TIG|date=June 1996|volume=12|issue=6|pages=201-4|pmid=8928221}}</ref> Large or multi-component transcription regulators with a range of mechanistic properties, including [[locus control region|locus control regions]], clustered open regulatory elements, and transcription initiation platforms, were observed shortly thereafter. <ref>{{cite journal|last1=Li|first1=Q|last2=Peterson|first2=KR|last3=Fang|first3=X|last4=Stamatoyannopoulos|first4=G|title=Locus control regions.|journal=Blood|date=1 November 2002|volume=100|issue=9|pages=3077-86|pmid=12384402}}</ref><ref>{{cite journal|last1=Grosveld|first1=F|last2=van Assendelft|first2=GB|last3=Greaves|first3=DR|last4=Kollias|first4=G|title=Position-independent, high-level expression of the human beta-globin gene in transgenic mice.|journal=Cell|date=24 December 1987|volume=51|issue=6|pages=975-85|pmid=3690667}}</ref><ref>{{cite journal|last1=Gaulton|first1=KJ|last2=Nammo|first2=T|last3=Pasquali|first3=L|last4=Simon|first4=JM|last5=Giresi|first5=PG|last6=Fogarty|first6=MP|last7=Panhuis|first7=TM|last8=Mieczkowski|first8=P|last9=Secchi|first9=A|last10=Bosco|first10=D|last11=Berney|first11=T|last12=Montanya|first12=E|last13=Mohlke|first13=KL|last14=Lieb|first14=JD|last15=Ferrer|first15=J|title=A map of open chromatin in human pancreatic islets.|journal=Nature genetics|date=March 2010|volume=42|issue=3|pages=255-9|pmid=20118932}}</ref><ref name="Koch2011">{{cite journal|last1=Koch|first1=F|last2=Fenouil|first2=R|last3=Gut|first3=M|last4=Cauchy|first4=P|last5=Albert|first5=TK|last6=Zacarias-Cabeza|first6=J|last7=Spicuglia|first7=S|last8=de la Chapelle|first8=AL|last9=Heidemann|first9=M|last10=Hintermair|first10=C|last11=Eick|first11=D|last12=Gut|first12=I|last13=Ferrier|first13=P|last14=Andrau|first14=JC|title=Transcription initiation platforms and GTF recruitment at tissue-specific enhancers and promoters.|journal=Nature structural & molecular biology|date=17 July 2011|volume=18|issue=8|pages=956-63|pmid=21765417}}</ref> More recent research has suggested that these different categories of regulatory elements may represent subtypes of super-enhancer. <ref name="Pott2015">{{cite journal|last1=Pott|first1=S|last2=Lieb|first2=JD|title=What are super-enhancers?|journal=Nature genetics|date=January 2015|volume=47|issue=1|pages=8-12|pmid=25547603}}</ref><ref name="Hnisz2013">{{cite journal|last1=Hnisz|first1=D|last2=Abraham|first2=BJ|last3=Lee|first3=TI|last4=Lau|first4=A|last5=Saint-André|first5=V|last6=Sigova|first6=AA|last7=Hoke|first7=HA|last8=Young|first8=RA|title=Super-enhancers in the control of cell identity and disease.|journal=Cell|date=7 November 2013|volume=155|issue=4|pages=934-47|pmid=24119843}}</ref>
+The [[transcriptional regulation|regulation of transcription]] by enhancers has been studied since the 1980s. <ref>{{cite journal|last1=Banerji|first1=J|last2=Rusconi|first2=S|last3=Schaffner|first3=W|title=Expression of a beta-globin gene is enhanced by remote SV40 DNA sequences.|journal=Cell|date=December 1981|volume=27|issue=2 Pt 1|pages=299-308|pmid=6277502}}</ref><ref>{{cite journal|last1=Benoist|first1=C|last2=Chambon|first2=P|title=In vivo sequence requirements of the SV40 early promotor region.|journal=Nature|date=26 March 1981|volume=290|issue=5804|pages=304-10|pmid=6259538}}</ref><ref>{{cite journal|last1=Gruss|first1=P|last2=Dhar|first2=R|last3=Khoury|first3=G|title=Simian virus 40 tandem repeated sequences as an element of the early promoter.|journal=Proceedings of the National Academy of Sciences of the United States of America|date=February 1981|volume=78|issue=2|pages=943-7|pmid=6262784}}</ref><ref>{{cite journal|last1=Evans|first1=T|last2=Felsenfeld|first2=G|last3=Reitman|first3=M|title=Control of globin gene transcription.|journal=Annual review of cell biology|date=1990|volume=6|pages=95-124|pmid=2275826}}</ref><ref>{{cite journal|last1=Cellier|first1=M|last2=Belouchi|first2=A|last3=Gros|first3=P|title=Resistance to intracellular infections: comparative genomic analysis of Nramp.|journal=Trends in genetics : TIG|date=June 1996|volume=12|issue=6|pages=201-4|pmid=8928221}}</ref> Large or multi-component transcription regulators with a range of mechanistic properties, including [[locus control region|locus control regions]], clustered open regulatory elements, and transcription initiation platforms, were observed shortly thereafter. <ref>{{cite journal|last1=Li|first1=Q|last2=Peterson|first2=KR|last3=Fang|first3=X|last4=Stamatoyannopoulos|first4=G|title=Locus control regions.|journal=Blood|date=1 November 2002|volume=100|issue=9|pages=3077-86|pmid=12384402}}</ref><ref>{{cite journal|last1=Grosveld|first1=F|last2=van Assendelft|first2=GB|last3=Greaves|first3=DR|last4=Kollias|first4=G|title=Position-independent, high-level expression of the human beta-globin gene in transgenic mice.|journal=Cell|date=24 December 1987|volume=51|issue=6|pages=975-85|pmid=3690667}}</ref><ref>{{cite journal|last1=Gaulton|first1=KJ|last2=Nammo|first2=T|last3=Pasquali|first3=L|last4=Simon|first4=JM|last5=Giresi|first5=PG|last6=Fogarty|first6=MP|last7=Panhuis|first7=TM|last8=Mieczkowski|first8=P|last9=Secchi|first9=A|last10=Bosco|first10=D|last11=Berney|first11=T|last12=Montanya|first12=E|last13=Mohlke|first13=KL|last14=Lieb|first14=JD|last15=Ferrer|first15=J|title=A map of open chromatin in human pancreatic islets.|journal=Nature genetics|date=March 2010|volume=42|issue=3|pages=255-9|pmid=20118932}}</ref><ref name="Koch2011">{{cite journal|last1=Koch|first1=F|last2=Fenouil|first2=R|last3=Gut|first3=M|last4=Cauchy|first4=P|last5=Albert|first5=TK|last6=Zacarias-Cabeza|first6=J|last7=Spicuglia|first7=S|last8=de la Chapelle|first8=AL|last9=Heidemann|first9=M|last10=Hintermair|first10=C|last11=Eick|first11=D|last12=Gut|first12=I|last13=Ferrier|first13=P|last14=Andrau|first14=JC|title=Transcription initiation platforms and GTF recruitment at tissue-specific enhancers and promoters.|journal=Nature structural & molecular biology|date=17 July 2011|volume=18|issue=8|pages=956-63|pmid=21765417}}</ref> More recent research has suggested that these different categories of regulatory elements may represent subtypes of super-enhancer. <ref name=Hnisz2013 /><ref name="Pott2015">{{cite journal|last1=Pott|first1=S|last2=Lieb|first2=JD|title=What are super-enhancers?|journal=Nature genetics|date=January 2015|volume=47|issue=1|pages=8-12|pmid=25547603}}</ref>
+In 2013, two labs identified large enhancers near several genes especially important for establishing cell identities. While [[Richard A. Young]] and colleagues identified super-enhancers, [[Francis Collins]] and colleagues identified stretch enhancers. <ref name= Whyte2013/><ref name=Parker2013 /> Both super-enhancers and stretch enhancers are clusters of enhancers that control cell-specific genes and may be largely synonymous. <ref name=Parker2013 /><ref name="Hnisz2015">{{cite journal|last1=Hnisz|first1=D|last2=Schuijers|first2=J|last3=Lin|first3=CY|last4=Weintraub|first4=AS|last5=Abraham|first5=BJ|last6=Lee|first6=TI|last7=Bradner|first7=JE|last8=Young|first8=RA|title=Convergence of developmental and oncogenic signaling pathways at transcriptional super-enhancers.|journal=Molecular cell|date=16 April 2015|volume=58|issue=2|pages=362-70|pmid=25801169}}</ref>
+As currently defined, the term “super-enhancer” was introduced by Young’s lab to describe regions identified in mouse [[embryonic stem cell|embryonic stem cells]] (ESCs). <ref name=Whyte2013 /> These particularly large, potent enhancer regions were found to control the genes that establish the embryonic stem cell identity, including [[Oct-4]], [[Sox2]], [[Homeobox protein NANOG|Nanog]], [[Klf4]], and [[Estrogen-related receptor beta|Esrrb]]. Perturbation of the super-enhancers associated with these genes showed a range of effects on their target genes’ expression. <ref name=Hnisz2015 /> Super-enhancers have been since identified near cell identity-regulators in a range of mouse and human tissues. <ref name=Parker2013 /><ref name=Hnisz2013 /><ref name="DiMicco2014">{{cite journal|last1=Di Micco|first1=R|last2=Fontanals-Cirera|first2=B|last3=Low|first3=V|last4=Ntziachristos|first4=P|last5=Yuen|first5=SK|last6=Lovell|first6=CD|last7=Dolgalev|first7=I|last8=Yonekubo|first8=Y|last9=Zhang|first9=G|last10=Rusinova|first10=E|last11=Gerona-Navarro|first11=G|last12=Cañamero|first12=M|last13=Ohlmeyer|first13=M|last14=Aifantis|first14=I|last15=Zhou|first15=MM|last16=Tsirigos|first16=A|last17=Hernando|first17=E|title=Control of embryonic stem cell identity by BRD4-dependent transcriptional elongation of super-enhancer-associated pluripotency genes.|journal=Cell reports|date=9 October 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+==Function==
+The enhancers comprising super-enhancers share the functions of enhancers, including binding transcription factor proteins, looping to target genes, and activating transcription. <ref name= Whyte2013/><ref name= Hnisz2013/><ref name= Pott2015/><ref name= Hnisz2015/> Three notable traits of enhancers comprising super-enhancers are their clustering in genomic proximity, their exceptional signal of transcription-regulating proteins, and their high frequency of physical interaction with each other. Perturbing the DNA of enhancers comprising super-enhancers showed a range of effects on the expression of cell identity genes, suggesting a complex relationship between the constituent enhancers. <ref name= Hnisz2015/>
+High levels of many transcription factors and co-factors are seen at super-enhancers (e.g., [[Cyclin-dependent kinase 7|CDK7]], [[BRD4]], and [[Mediator (coactivator)||Mediator]]). <ref name= Whyte2013/><ref name= Hnisz2013/><ref name= Kwiatkowski2014/><ref name= Lovén2013 /><ref name= Christensen2014/><ref name= Chipumuro2014/><ref name= Pott2015/>
+This high concentration of transcription-regulating proteins suggests why their target genes tend to be more highly expressed than other classes of genes. However, housekeeping genes tend to be more highly expressed than super-enhancer—associated genes. <ref name= Whyte2013/>
+Super-enhancers may have been evolved at key cell identity genes to render the transcription of these genes responsive to an array of external cues. <ref name= Hnisz2015/> The enhancers comprising a super-enhancer can each be responsive to different signals, which allows the transcription of a single gene to be regulated by multiple signaling pathways. <ref name= Hnisz2015/> Pathways seen to regulate their target genes using super-enhancers include [[Wnt signaling pathway |Wnt]], [[TGF beta signaling pathway|TGFb]], [[Leukemia inhibitory factor|LIF]], [[Brain-derived neurotrophic factor|BDNF]], and [[Notch signaling pathway|NOTCH]]. <ref name= Hnisz2015/><ref name="Joo2016">{{cite journal|last1=Joo|first1=JY|last2=Schaukowitch|first2=K|last3=Farbiak|first3=L|last4=Kilaru|first4=G|last5=Kim|first5=TK|title=Stimulus-specific combinatorial functionality of neuronal c-fos enhancers.|journal=Nature neuroscience|date=January 2016|volume=19|issue=1|pages=75-83|pmid=26595656}}</ref><ref name="Herranz2014">{{cite journal|last1=Herranz|first1=D|last2=Ambesi-Impiombato|first2=A|last3=Palomero|first3=T|last4=Schnell|first4=SA|last5=Belver|first5=L|last6=Wendorff|first6=AA|last7=Xu|first7=L|last8=Castillo-Martin|first8=M|last9=Llobet-Navás|first9=D|last10=Cordon-Cardo|first10=C|last11=Clappier|first11=E|last12=Soulier|first12=J|last13=Ferrando|first13=AA|title=A NOTCH1-driven MYC enhancer promotes T cell development, transformation and acute lymphoblastic leukemia.|journal=Nature medicine|date=October 2014|volume=20|issue=10|pages=1130-7|pmid=25194570}}</ref><ref name="Wang2014">{{cite journal|last1=Wang|first1=H|last2=Zang|first2=C|last3=Taing|first3=L|last4=Arnett|first4=KL|last5=Wong|first5=YJ|last6=Pear|first6=WS|last7=Blacklow|first7=SC|last8=Liu|first8=XS|last9=Aster|first9=JC|title=NOTCH1-RBPJ complexes drive target gene expression through dynamic interactions with superenhancers.|journal=Proceedings of the National Academy of Sciences of the United States of America|date=14 January 2014|volume=111|issue=2|pages=705-10|pmid=24374627}}</ref><ref name="Yashiro-Ohtani2014">{{cite journal|last1=Yashiro-Ohtani|first1=Y|last2=Wang|first2=H|last3=Zang|first3=C|last4=Arnett|first4=KL|last5=Bailis|first5=W|last6=Ho|first6=Y|last7=Knoechel|first7=B|last8=Lanauze|first8=C|last9=Louis|first9=L|last10=Forsyth|first10=KS|last11=Chen|first11=S|last12=Chung|first12=Y|last13=Schug|first13=J|last14=Blobel|first14=GA|last15=Liebhaber|first15=SA|last16=Bernstein|first16=BE|last17=Blacklow|first17=SC|last18=Liu|first18=XS|last19=Aster|first19=JC|last20=Pear|first20=WS|title=Long-range enhancer activity determines Myc sensitivity to Notch inhibitors in T cell leukemia.|journal=Proceedings of the National Academy of Sciences of the United States of America|date=18 November 2014|volume=111|issue=46|pages=E4946-53|pmid=25369933}}</ref> The constituent enhancers of super-enhancers physically interact with each other and their target genes. <ref name= Dowen2014/><ref name= Ji2016/><ref name="Hnisz2016">{{cite journal|last1=Hnisz|first1=D|last2=Weintraub|first2=AS|last3=Day|first3=DS|last4=Valton|first4=AL|last5=Bak|first5=RO|last6=Li|first6=CH|last7=Goldmann|first7=J|last8=Lajoie|first8=BR|last9=Fan|first9=ZP|last10=Sigova|first10=AA|last11=Reddy|first11=J|last12=Borges-Rivera|first12=D|last13=Lee|first13=TI|last14=Jaenisch|first14=R|last15=Porteus|first15=MH|last16=Dekker|first16=J|last17=Young|first17=RA|title=Activation of proto-oncogenes by disruption of chromosome neighborhoods.|journal=Science (New York, N.Y.)|date=25 March 2016|volume=351|issue=6280|pages=1454-8|pmid=26940867}}</ref>
+==Relevance to Disease==
+Mutations in super-enhancers have been noted in various diseases, including cancers, type 1 diabetes, Alzheimer’s disease, lupus, rheumatoid arthritis, multiple sclerosis, systemic scleroderma, primary biliary cirrhosis, Crohn’s disease, Graves disease, vitiligo, and atrial fibrillation. <ref name=Parker2013 /><ref name=Hnisz2013 /><ref name=Lovén2013 /><ref name=Vahedi2015 /><ref name=Pasquali2014 /><ref name=Kaikkonen2014 /><ref name="Mansour2014">{{cite journal|last1=Mansour|first1=MR|last2=Abraham|first2=BJ|last3=Anders|first3=L|last4=Berezovskaya|first4=A|last5=Gutierrez|first5=A|last6=Durbin|first6=AD|last7=Etchin|first7=J|last8=Lawton|first8=L|last9=Sallan|first9=SE|last10=Silverman|first10=LB|last11=Loh|first11=ML|last12=Hunger|first12=SP|last13=Sanda|first13=T|last14=Young|first14=RA|last15=Look|first15=AT|title=Oncogene regulation. An oncogenic super-enhancer formed through somatic mutation of a noncoding intergenic element.|journal=Science (New York, N.Y.)|date=12 December 2014|volume=346|issue=6215|pages=1373-7|pmid=25394790}}</ref><ref name="Cavalli2016">{{cite journal|last1=Cavalli|first1=G|last2=Hayashi|first2=M|last3=Jin|first3=Y|last4=Yorgov|first4=D|last5=Santorico|first5=SA|last6=Holcomb|first6=C|last7=Rastrou|first7=M|last8=Erlich|first8=H|last9=Tengesdal|first9=IW|last10=Dagna|first10=L|last11=Neff|first11=CP|last12=Palmer|first12=BE|last13=Spritz|first13=RA|last14=Dinarello|first14=CA|title=MHC class II super-enhancer increases surface expression of HLA-DR and HLA-DQ and affects cytokine production in autoimmune vitiligo.|journal=Proceedings of the National Academy of Sciences of the United States of America|date=2 February 2016|volume=113|issue=5|pages=1363-8|pmid=26787888}}</ref><ref name="Farh2015">{{cite journal|last1=Farh|first1=KK|last2=Marson|first2=A|last3=Zhu|first3=J|last4=Kleinewietfeld|first4=M|last5=Housley|first5=WJ|last6=Beik|first6=S|last7=Shoresh|first7=N|last8=Whitton|first8=H|last9=Ryan|first9=RJ|last10=Shishkin|first10=AA|last11=Hatan|first11=M|last12=Carrasco-Alfonso|first12=MJ|last13=Mayer|first13=D|last14=Luckey|first14=CJ|last15=Patsopoulos|first15=NA|last16=De Jager|first16=PL|last17=Kuchroo|first17=VK|last18=Epstein|first18=CB|last19=Daly|first19=MJ|last20=Hafler|first20=DA|last21=Bernstein|first21=BE|title=Genetic and epigenetic fine mapping of causal autoimmune disease variants.|journal=Nature|date=19 February 2015|volume=518|issue=7539|pages=337-43|pmid=25363779}}</ref><ref name="Weinstein2014">{{cite journal|last1=Weinstein|first1=JS|last2=Lezon-Geyda|first2=K|last3=Maksimova|first3=Y|last4=Craft|first4=S|last5=Zhang|first5=Y|last6=Su|first6=M|last7=Schulz|first7=VP|last8=Craft|first8=J|last9=Gallagher|first9=PG|title=Global transcriptome analysis and enhancer landscape of human primary T follicular helper and T effector lymphocytes.|journal=Blood|date=11 December 2014|volume=124|issue=25|pages=3719-29|pmid=25331115}}</ref><ref name="Oldridge2015">{{cite journal|last1=Oldridge|first1=DA|last2=Wood|first2=AC|last3=Weichert-Leahey|first3=N|last4=Crimmins|first4=I|last5=Sussman|first5=R|last6=Winter|first6=C|last7=McDaniel|first7=LD|last8=Diamond|first8=M|last9=Hart|first9=LS|last10=Zhu|first10=S|last11=Durbin|first11=AD|last12=Abraham|first12=BJ|last13=Anders|first13=L|last14=Tian|first14=L|last15=Zhang|first15=S|last16=Wei|first16=JS|last17=Khan|first17=J|last18=Bramlett|first18=K|last19=Rahman|first19=N|last20=Capasso|first20=M|last21=Iolascon|first21=A|last22=Gerhard|first22=DS|last23=Guidry Auvil|first23=JM|last24=Young|first24=RA|last25=Hakonarson|first25=H|last26=Diskin|first26=SJ|last27=Look|first27=AT|last28=Maris|first28=JM|title=Genetic predisposition to neuroblastoma mediated by a LMO1 super-enhancer polymorphism.|journal=Nature|date=17 December 2015|volume=528|issue=7582|pages=418-21|pmid=26560027}}</ref>  A similar enrichment in disease-associated sequence variation has also been observed for stretch enhancers. <ref name=Parker2013 />
+Super-enhancers may play important roles in the misregulation of gene expression in cancer. 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journal|last1=Kennedy|first1=AL|last2=Vallurupalli|first2=M|last3=Chen|first3=L|last4=Crompton|first4=B|last5=Cowley|first5=G|last6=Vazquez|first6=F|last7=Weir|first7=BA|last8=Tsherniak|first8=A|last9=Parasuraman|first9=S|last10=Kim|first10=S|last11=Alexe|first11=G|last12=Stegmaier|first12=K|title=Functional, chemical genomic, and super-enhancer screening identify sensitivity to cyclin D1/CDK4 pathway inhibition in Ewing sarcoma.|journal=Oncotarget|date=6 October 2015|volume=6|issue=30|pages=30178-93|pmid=26337082}}</ref><ref name="Tomazou2015">{{cite journal|last1=Tomazou|first1=EM|last2=Sheffield|first2=NC|last3=Schmidl|first3=C|last4=Schuster|first4=M|last5=Schönegger|first5=A|last6=Datlinger|first6=P|last7=Kubicek|first7=S|last8=Bock|first8=C|last9=Kovar|first9=H|title=Epigenome mapping reveals distinct modes of gene regulation and widespread enhancer reprogramming by the oncogenic fusion protein EWS-FLI1.|journal=Cell reports|date=24 February 2015|volume=10|issue=7|pages=1082-95|pmid=25704812}}</ref><ref name="Nabet2015">{{cite journal|last1=Nabet|first1=B|last2=Ó Broin|first2=P|last3=Reyes|first3=JM|last4=Shieh|first4=K|last5=Lin|first5=CY|last6=Will|first6=CM|last7=Popovic|first7=R|last8=Ezponda|first8=T|last9=Bradner|first9=JE|last10=Golden|first10=AA|last11=Licht|first11=JD|title=Deregulation of the Ras-Erk Signaling Axis Modulates the Enhancer Landscape.|journal=Cell reports|date=25 August 2015|volume=12|issue=8|pages=1300-13|pmid=26279576}}</ref><ref name="Zhang2016">{{cite journal|last1=Zhang|first1=X|last2=Choi|first2=PS|last3=Francis|first3=JM|last4=Imielinski|first4=M|last5=Watanabe|first5=H|last6=Cherniack|first6=AD|last7=Meyerson|first7=M|title=Identification of focally amplified lineage-specific super-enhancers in human epithelial cancers.|journal=Nature genetics|date=February 2016|volume=48|issue=2|pages=176-82|pmid=26656844}}</ref> Acquired super-enhancers may thus be [[biomarker|biomarkers]] that could be useful for diagnosis and therapeutic intervention. <ref name=Hnisz2015 />
-In 2013, two labs identified large enhancers near several genes especially important for establishing cell identities. While [[Richard A. Young]] and colleagues identified super-enhancers, [[Francis Collins]] and colleagues identified stretch enhancers. <ref name="Whyte2013">{{cite journal|last1=Whyte|first1=WA|last2=Orlando|first2=DA|last3=Hnisz|first3=D|last4=Abraham|first4=BJ|last5=Lin|first5=CY|last6=Kagey|first6=MH|last7=Rahl|first7=PB|last8=Lee|first8=TI|last9=Young|first9=RA|title=Master transcription factors and mediator establish super-enhancers at key cell identity genes.|journal=Cell|date=11 April 2013|volume=153|issue=2|pages=307-19|pmid=23582322}}</ref><ref name="Parker2013">{{cite journal|last1=Parker|first1=SC|last2=Stitzel|first2=ML|last3=Taylor|first3=DL|last4=Orozco|first4=JM|last5=Erdos|first5=MR|last6=Akiyama|first6=JA|last7=van Bueren|first7=KL|last8=Chines|first8=PS|last9=Narisu|first9=N|last10=NISC Comparative Sequencing|first10=Program|last11=Black|first11=BL|last12=Visel|first12=A|last13=Pennacchio|first13=LA|last14=Collins|first14=FS|last15=National Institutes of Health Intramural Sequencing Center Comparative Sequencing Program|first15=Authors|last16=NISC Comparative Sequencing Program|first16=Authors|title=Chromatin stretch enhancer states drive cell-specific gene regulation and harbor human disease risk variants.|journal=Proceedings of the National Academy of Sciences of the United States of America|date=29 October 2013|volume=110|issue=44|pages=17921-6|pmid=24127591}}</ref>  Both super-enhancers and stretch enhancers are clusters of enhancers that control cell-specific genes and may be largely synonymous. <ref name=Parker2013 /><ref name="Hnisz2015">{{cite journal|last1=Hnisz|first1=D|last2=Schuijers|first2=J|last3=Lin|first3=CY|last4=Weintraub|first4=AS|last5=Abraham|first5=BJ|last6=Lee|first6=TI|last7=Bradner|first7=JE|last8=Young|first8=RA|title=Convergence of developmental and oncogenic signaling pathways at transcriptional super-enhancers.|journal=Molecular cell|date=16 April 2015|volume=58|issue=2|pages=362-70|pmid=25801169}}</ref>
+Proteins enriched at super-enhancers include the targets of small molecules that target transcription-regulating proteins and have been deployed against cancers.  <ref name= Kwiatkowski2014 /><ref name= Lovén2013 /><ref name=Vahedi2015 /><ref name="Porcher2015">{{cite journal|last1=Porcher|first1=C|title=Toward a BETter grasp of acetyl-lysine readers.|journal=Blood|date=30 April 2015|volume=125|issue=18|pages=2739-41|pmid=25931578}}</ref> For instance, super-enhancers rely on exceptional amounts of CDK7, and, in cancer, multiple papers report the loss of expression of their target genes when cells are treated with the CDK7 inhibitor THZ1.<ref name= Kwiatkowski2014 /><ref name= Christensen2014 /><ref name= Chipumuro2014 /><ref name="Wang2015">{{cite journal|last1=Wang|first1=Y|last2=Zhang|first2=T|last3=Kwiatkowski|first3=N|last4=Abraham|first4=BJ|last5=Lee|first5=TI|last6=Xie|first6=S|last7=Yuzugullu|first7=H|last8=Von|first8=T|last9=Li|first9=H|last10=Lin|first10=Z|last11=Stover|first11=DG|last12=Lim|first12=E|last13=Wang|first13=ZC|last14=Iglehart|first14=JD|last15=Young|first15=RA|last16=Gray|first16=NS|last17=Zhao|first17=JJ|title=CDK7-dependent transcriptional addiction in triple-negative breast cancer.|journal=Cell|date=24 September 2015|volume=163|issue=1|pages=174-86|pmid=26406377}}</ref> Similarly, super-enhancers are enriched in the target of the JQ1 small molecule, BRD4, so treatment with [[JQ1]] causes exceptional losses in expression for super-enhancer—associated genes. <ref name= Lovén2013 />
-As currently defined, the term “super-enhancer” was introduced by Young’s lab to describe regions identified in mouse [[embryonic stem cell|embryonic stem cells]] (ESCs). <ref name=Whyte2013 /> These particularly large, potent enhancer regions were found to control the genes that establish the embryonic stem cell identity, including [[Oct-4]], [[Sox2]], [[Homeobox protein NANOG|Nanog]], [[Klf4]], and [[Estrogen-related receptor beta|Esrrb]]. Perturbation of the super-enhancers associated with these genes showed a range of effects on their target genes’ expression. <ref name=Hnisz2015 /> Super-enhancers have been since identified near cell identity-regulators in a range of mouse and human tissues. <ref name=Hnisz2013 /><ref name="DiMicco2014">{{cite journal|last1=Di Micco|first1=R|last2=Fontanals-Cirera|first2=B|last3=Low|first3=V|last4=Ntziachristos|first4=P|last5=Yuen|first5=SK|last6=Lovell|first6=CD|last7=Dolgalev|first7=I|last8=Yonekubo|first8=Y|last9=Zhang|first9=G|last10=Rusinova|first10=E|last11=Gerona-Navarro|first11=G|last12=Cañamero|first12=M|last13=Ohlmeyer|first13=M|last14=Aifantis|first14=I|last15=Zhou|first15=MM|last16=Tsirigos|first16=A|last17=Hernando|first17=E|title=Control of embryonic stem cell identity by BRD4-dependent transcriptional elongation of super-enhancer-associated pluripotency genes.|journal=Cell reports|date=9 October 2014|volume=9|issue=1|pages=234-47|pmid=25263550}}</ref><ref 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 ==Identification==
-Super-enhancers have been most commonly identified by locating genomic regions that are highly enriched in [[ChIP-sequencing|ChIP-Seq]] signal. ChIP-Seq experiments targeting master transcription factors and co-factors like [[Mediator (coactivator)|Mediator]]  or [[BRD4]] have been used, but the most frequently used is H3K27ac-marked [[Nucleosome|nucleosomes]]. <ref name=Hnisz2013 /><ref name=Whyte2013 /><ref name="Lovén2013">{{cite journal|last1=Lovén|first1=J|last2=Hoke|first2=HA|last3=Lin|first3=CY|last4=Lau|first4=A|last5=Orlando|first5=DA|last6=Vakoc|first6=CR|last7=Bradner|first7=JE|last8=Lee|first8=TI|last9=Young|first9=RA|title=Selective inhibition of tumor oncogenes by disruption of super-enhancers.|journal=Cell|date=11 April 2013|volume=153|issue=2|pages=320-34|pmid=23582323}}</ref><ref name="Wei2016">{{cite journal|last1=Wei|first1=Y|last2=Zhang|first2=S|last3=Shang|first3=S|last4=Zhang|first4=B|last5=Li|first5=S|last6=Wang|first6=X|last7=Wang|first7=F|last8=Su|first8=J|last9=Wu|first9=Q|last10=Liu|first10=H|last11=Zhang|first11=Y|title=SEA: a super-enhancer archive.|journal=Nucleic acids research|date=4 January 2016|volume=44|issue=D1|pages=D172-9|pmid=26578594}}</ref><ref name="Khan2016">{{cite journal|last1=Khan|first1=A|last2=Zhang|first2=X|title=dbSUPER: a database of super-enhancers in mouse and human genome.|journal=Nucleic acids research|date=4 January 2016|volume=44|issue=D1|pages=D164-71|pmid=26438538}}</ref><ref name="Creyghton2010">{{cite journal|last1=Creyghton|first1=MP|last2=Cheng|first2=AW|last3=Welstead|first3=GG|last4=Kooistra|first4=T|last5=Carey|first5=BW|last6=Steine|first6=EJ|last7=Hanna|first7=J|last8=Lodato|first8=MA|last9=Frampton|first9=GM|last10=Sharp|first10=PA|last11=Boyer|first11=LA|last12=Young|first12=RA|last13=Jaenisch|first13=R|title=Histone H3K27ac separates active from poised enhancers and predicts developmental state.|journal=Proceedings of the National Academy of Sciences of the United States of America|date=14 December 2010|volume=107|issue=50|pages=21931-6|pmid=21106759}}</ref>  The program “[https://bitbucket.org/young_computation/rose/ ROSE]” (Rank Ordering of Super-Enhancers) is used to identify super-enhancers from ChIP-Seq data. This program stitches together previously identified enhancer regions and ranks these stitched enhancers by their ChIP-Seq signal. <ref name=Whyte2013 /> The stitching distance selected to combine multiple individual enhancers into larger domains can vary. Because some markers of enhancer activity also are enriched in [[Promoter (genetics)|promoters]], regions within promoters of genes can be disregarded. ROSE separates super-enhancers from typical enhancers by their exceptional enrichment in a mark of enhancer activity.
+Super-enhancers have been most commonly identified by locating genomic regions that are highly enriched in [[ChIP-sequencing|ChIP-Seq]] signal. ChIP-Seq experiments targeting master transcription factors and co-factors like Mediator or BRD4 have been used, but the most frequently used is H3K27ac-marked [[Nucleosome|nucleosomes]]. <ref name=Whyte2013 /><ref name=Hnisz2013 /><ref name= Lovén2013 /><ref name="Wei2016">{{cite journal|last1=Wei|first1=Y|last2=Zhang|first2=S|last3=Shang|first3=S|last4=Zhang|first4=B|last5=Li|first5=S|last6=Wang|first6=X|last7=Wang|first7=F|last8=Su|first8=J|last9=Wu|first9=Q|last10=Liu|first10=H|last11=Zhang|first11=Y|title=SEA: a super-enhancer archive.|journal=Nucleic acids research|date=4 January 2016|volume=44|issue=D1|pages=D172-9|pmid=26578594}}</ref><ref name="Khan2016">{{cite journal|last1=Khan|first1=A|last2=Zhang|first2=X|title=dbSUPER: a database of super-enhancers in mouse and human genome.|journal=Nucleic acids research|date=4 January 2016|volume=44|issue=D1|pages=D164-71|pmid=26438538}}</ref><ref name="Creyghton2010">{{cite journal|last1=Creyghton|first1=MP|last2=Cheng|first2=AW|last3=Welstead|first3=GG|last4=Kooistra|first4=T|last5=Carey|first5=BW|last6=Steine|first6=EJ|last7=Hanna|first7=J|last8=Lodato|first8=MA|last9=Frampton|first9=GM|last10=Sharp|first10=PA|last11=Boyer|first11=LA|last12=Young|first12=RA|last13=Jaenisch|first13=R|title=Histone H3K27ac separates active from poised enhancers and predicts developmental state.|journal=Proceedings of the National Academy of Sciences of the United States of America|date=14 December 2010|volume=107|issue=50|pages=21931-6|pmid=21106759}}</ref>  The program “[https://bitbucket.org/young_computation/rose/ ROSE]” (Rank Ordering of Super-Enhancers) is commonly used to identify super-enhancers from ChIP-Seq data. This program stitches together previously identified enhancer regions and ranks these stitched enhancers by their ChIP-Seq signal. <ref name=Whyte2013 /> The stitching distance selected to combine multiple individual enhancers into larger domains can vary. Because some markers of enhancer activity also are enriched in [[Promoter (genetics)|promoters]], regions within promoters of genes can be disregarded. ROSE separates super-enhancers from typical enhancers by their exceptional enrichment in a mark of enhancer activity.
-== References ==
+==References==
 {{reflist}}