Enhancer RNAs: A missing regulatory layer in gene transcription
|
摘要
Enhancers and super-enhancers exert indispensable roles in maintaining cell identity through spatiotemporally regulating gene transcription. Meanwhile, active enhancers and super-enhancers also produce transcripts termed enhancer RNAs(eRNAs) from their DNA elements. Although enhancers have been identified for more than 30 years, widespread transcription from enhancers are just discovered by genome-wide sequencing and considered as the key to understand longstanding questions in gene transcription. RNA-transcribed enhancers are marked by histone modifications such as H3K4m1/2 and H3K27Ac, and enriched with transcription regulatory factors such as LDTFs, P300, CBP, BRD4 and MED1. Those regulatory factors might constitute a Mega-Trans-like complex to potently activate enhancers. Compared to mRNAs, eRNAs are quite unstable and play roles at local.Functionally, it has been shown that e RNAs promote formation of enhancer-promoter loops. Several studies also demonstrated that eRNAs help the binding of RNA polymerase II(RNAPII) or transition of paused RNAPII by de-association of the negative elongation factor(NELF) complex. Nevertheless, these proposed mechanisms are not universally accepted and still under controversy. Here, we comprehensively summarize the reported findings and make perspectives for future exploration. We also believe that super-enhancer derived RNAs(seRNAs) might be informative to understand the nature of super-enhancers.
Enhancers and super-enhancers exert indispensable roles in maintaining cell identity through spatiotemporally regulating gene transcription. Meanwhile, active enhancers and super-enhancers also produce transcripts termed enhancer RNAs(eRNAs) from their DNA elements. Although enhancers have been identified for more than 30 years, widespread transcription from enhancers are just discovered by genome-wide sequencing and considered as the key to understand longstanding questions in gene transcription. RNA-transcribed enhancers are marked by histone modifications such as H3K4m1/2 and H3K27Ac, and enriched with transcription regulatory factors such as LDTFs, P300, CBP, BRD4 and MED1. Those regulatory factors might constitute a Mega-Trans-like complex to potently activate enhancers. Compared to mRNAs, eRNAs are quite unstable and play roles at local.Functionally, it has been shown that e RNAs promote formation of enhancer-promoter loops. Several studies also demonstrated that eRNAs help the binding of RNA polymerase II(RNAPII) or transition of paused RNAPII by de-association of the negative elongation factor(NELF) complex. Nevertheless, these proposed mechanisms are not universally accepted and still under controversy. Here, we comprehensively summarize the reported findings and make perspectives for future exploration. We also believe that super-enhancer derived RNAs(seRNAs) might be informative to understand the nature of super-enhancers.
Enhancers and super-enhancers exert indispensable roles in maintaining cell identity through spatiotemporally regulating gene transcription. Meanwhile, active enhancers and super-enhancers also produce transcripts termed enhancer RNAs(eRNAs) from their DNA elements. Although enhancers have been identified for more than 30 years, widespread transcription from enhancers are just discovered by genome-wide sequencing and considered as the key to understand longstanding questions in gene transcription. RNA-transcribed enhancers are marked by histone modifications such as H3K4m1/2 and H3K27Ac, and enriched with transcription regulatory factors such as LDTFs, P300, CBP, BRD4 and MED1. Those regulatory factors might constitute a Mega-Trans-like complex to potently activate enhancers. Compared to mRNAs, eRNAs are quite unstable and play roles at local.Functionally, it has been shown that e RNAs promote formation of enhancer-promoter loops. Several studies also demonstrated that eRNAs help the binding of RNA polymerase II(RNAPII) or transition of paused RNAPII by de-association of the negative elongation factor(NELF) complex. Nevertheless, these proposed mechanisms are not universally accepted and still under controversy. Here, we comprehensively summarize the reported findings and make perspectives for future exploration. We also believe that super-enhancer derived RNAs(seRNAs) might be informative to understand the nature of super-enhancers.
引文
Altshuler,D.L.,Durbin,R.M.,Abecasis,G.R.,Bentley,D.R.,Chakravarti,A.,Clark,A.G.,Collins,F.S.,De La Vega,F.M.,Donnelly,P.,et al.(2010).A map of human genome variation from population-scale sequencing.Nature 467,1061-1073.
Abraham,B.J.,Hnisz,D.,Weintraub,A.S.,Kwiatkowski,N.,Li,C.H.,Li,Z.,Weichert-Leahey,N.,Rahman,S.,Liu,Y.,Etchin,J.,et al.(2017).Small genomic insertions form enhancers that misregulate oncogenes.Nat Commun 8,14385.
Akhtar-Zaidi,B.,Cowper-Sal·lari,R.,Corradin,O.,Saiakhova,A.,Bartels,C.F.,Balasubramanian,D.,Myeroff,L.,Lutterbaugh,J.,Jarrar,A.,Kalady,M.F.,et al.(2012).Epigenomic enhancer profiling defines a signature of colon cancer.Science 336,736-739.
Allen,M.A.,Andrysik,Z.,Dengler,V.L.,Mellert,H.S.,Guarnieri,A.,Freeman,J.A.,Sullivan,K.D.,Galbraith,M.D.,Luo,X.,Kraus,W.L.,et al.(2014).Global analysis of p53-regulated transcription identifies its direct targets and unexpected regulatory mechanisms.eLife 3,e02200.
Alvarez-Dominguez,J.R.,Knoll,M.,Gromatzky,A.A.,and Lodish,H.F.(2017).The super-enhancer-derived alncRNA-EC7/bloodlinc potentiates red blood cell development in trans.Cell Rep 19,2503-2514.
Andersson,R.,Gebhard,C.,Miguel-Escalada,I.,Hoof,I.,Bornholdt,J.,Boyd,M.,Chen,Y.,Zhao,X.,Schmidl,C.,Suzuki,T.,et al.(2014).An atlas of active enhancers across human cell types and tissues.Nature507,455-461.
Arner,E.,Daub,C.O.,Vitting-Seerup,K.,Andersson,R.,Lilje,B.,Drabl?s,F.,Lennartsson,A.,R?nnerblad,M.,Hrydziuszko,O.,Vitezic,M.,et al.(2015).Transcribed enhancers lead waves of coordinated transcription in transitioning mammalian cells.Science 347,1010-1014.
Bales,D.J.(1990).On predicting the future of dentistry.Oper Dent 15,121.
Banerji,J.,Rusconi,S.,and Schaffner,W.(1981).Expression of aβ-globin gene is enhanced by remote SV40 DNA sequences.Cell 27,299-308.
Blackwood,E.M.,and Kadonaga,J.T.(1998).Going the distance:a current view of enhancer action.Science 281,60-63.
Chapuy,B.,McKeown,M.R.,Lin,C.Y.,Monti,S.,Roemer,M.G.M.,Qi,J.,Rahl,P.B.,Sun,H.H.,Yeda,K.T.,Doench,J.G.,et al.(2013).Discovery and characterization of super-enhancer-associated dependencies in diffuse large B cell lymphoma.Cancer Cell 24,777-790.
Cheng,H.,Dou,X.,and Han,J.D.J.(2016).Understanding superenhancers.Sci China Life Sci 59,277-280.
Cheng,J.H.,Pan,D.Z.C.,Tsai,Z.T.Y.,and Tsai,H.K.(2015).Genomewide analysis of enhancer RNA in gene regulation across 12 mouse tissues.Sci Rep 5,12648.
Chokas,A.L.,Bickford,J.S.,Barilovits,S.J.,Rogers,R.J.,Qiu,X.,Newsom,K.J.,Beachy,D.E.,and Nick,H.S.(2014).A TEAD1/p65complex regulates the eutherian-conserved MnSOD intronic enhancer,eRNA transcription and the innate immune response.Biochim Biophys Acta 1839,1205-1216.
Collis,P.,Antoniou,M.,and Grosveld,F.(1990).Definition of the minimal requirements within the human beta-globin gene and the dominant control region for high level expression..EMBO J 9,233-240.
Corradin,O.,Saiakhova,A.,Akhtar-Zaidi,B.,Myeroff,L.,Willis,J.,Cowper-Sal{middle dot}lari,R.,Lupien,M.,Markowitz,S.,and Scacheri,P.C.(2014).Combinatorial effects of multiple enhancer variants in linkage disequilibrium dictate levels of gene expression to confer susceptibility to common traits.Genome Res 24,1-13.
De Santa,F.,Barozzi,I.,Mietton,F.,Ghisletti,S.,Polletti,S.,Tusi,B.K.,Muller,H.,Ragoussis,J.,Wei,C.L.,and Natoli,G.(2010).A large fraction of extragenic RNA pol II transcription sites overlap enhancers.PLoS Biol 8,e1000384.
Djebali,S.,Davis,C.A.,Merkel,A.,Dobin,A.,Lassmann,T.,Mortazavi,A.,Tanzer,A.,Lagarde,J.,Lin,W.,Schlesinger,F.,et al.(2012).Landscape of transcription in human cells.Nature 489,101-108.
Dorighi,K.M.,Swigut,T.,Henriques,T.,Bhanu,N.V.,Scruggs,B.S.,Nady,N.,Still Ii,C.D.,Garcia,B.A.,Adelman,K.,and Wysocka,J.(2017).Mll3 and Mll4 facilitate enhancer RNA synthesis and transcription from promoters independently of H3K4 monomethylation.Mol Cell 66,568-576.e4.
Dukler,N.,Gulko,B.,Huang,Y.F.,and Siepel,A.(2017).Is a superenhancer greater than the sum of its parts?Nat Genet 49,2-3.
ENCODE Project Consortium.(2012).An integrated encyclopedia of DNAelements in the human genome.Nature 489,57-74.
Ernst,J.,Kheradpour,P.,Mikkelsen,T.S.,Shoresh,N.,Ward,L.D.,Epstein,C.B.,Zhang,X.,Wang,L.,Issner,R.,Coyne,M.,et al.(2011).Mapping and analysis of chromatin state dynamics in nine human cell types.Nature 473,43-49.
Feng,J.,Bi,C.,Clark,B.S.,Mady,R.,Shah,P.,and Kohtz,J.D.(2006).The Evf-2 noncoding RNA is transcribed from the Dlx-5/6ultraconserved region and functions as a Dlx-2 transcriptional coactivator.Genes Dev 20,1470-1484.
Flynn,R.A.,Do,B.T.,Rubin,A.J.,Calo,E.,Lee,B.,Kuchelmeister,H.,Rale,M.,Chu,C.,Kool,E.T.,Wysocka,J.,et al.(2016).7SK-BAF axis controls pervasive transcription at enhancers.Nat Struct Mol Biol 23,231-238.
Hah,N.,Benner,C.,Chong,L.W.,Yu,R.T.,Downes,M.,and Evans,R.M.(2015).Inflammation-sensitive super enhancers form domains of coordinately regulated enhancer RNAs.Proc Natl Acad Sci USA 112,E297-E302.
Hah,N.,Murakami,S.,Nagari,A.,Danko,C.G.,and Kraus,W.L.(2013).Enhancer transcripts mark active estrogen receptor binding sites.Genome Res 23,1210-1223.
Harris,H.(1959).Turnover of nuclear and cytoplasmic ribonucleic acid in two types of animal cell,with some further observations on the nucleolus.Biochem J 73,362-369.
He,H.,Li,W.,Wu,D.,Nagy,R.,Liyanarachchi,S.,Akagi,K.,Jendrzejewski,J.,Jiao,H.,Hoag,K.,Wen,B.,et al.(2013).Ultrarare mutation in long-range enhancer predisposes to thyroid carcinoma with high penetrance.PLoS ONE 8,e61920.
Heintzman,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.(2009).Histone modifications at human enhancers reflect global cell-typespecific gene expression.Nature 459,108-112.
Henley,C.M.Iii,Owings,M.H.,Stagner,B.B.,Martin,G.K.,and Lonsbury-Martin,B.L.(1990).Postnatal development of 2?1-?2otoacoustic emissions in pigmented rat.Hear Res 43,141-148.
Hsieh,C.L.,Fei,T.,Chen,Y.,Li,T.,Gao,Y.,Wang,X.,Sun,T.,Sweeney,C.J.,Lee,G.S.M.,Chen,S.,et al.(2014).Enhancer RNAs participate in androgen receptor-driven looping that selectively enhances gene activation.Proc Natl Acad Sci USA 111,7319-7324.
Isoda,T.,Moore,A.J.,He,Z.,Chandra,V.,Aida,M.,Denholtz,M.,Piet van Hamburg,J.,Fisch,K.M.,Chang,A.N.,Fahl,S.P.,et al.(2017).Non-coding transcription instructs chromatin folding and compartmentalization to dictate enhancer-promoter communication and T cell fate.Cell 171,103-119.e18.
Jeong,M.,and Goodell,M.A.Noncoding regulatory RNAs in hematopoiesis.(2016).Curr Top Dev Biol 118,245-270.
Kaikkonen,M.U.,Spann,N.J.,Heinz,S.,Romanoski,C.E.,Allison,K.A.,Stender,J.D.,Chun,H.B.,Tough,D.F.,Prinjha,R.K.,Benner,C.,et al.(2013).Remodeling of the enhancer landscape during macrophage activation is coupled to enhancer transcription.Mol Cell 51,310-325.
Kim,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.(2010).Widespread transcription at neuronal activity-regulated enhancers.Nature 465,182-187.
Koch,F.,Fenouil,R.,Gut,M.,Cauchy,P.,Albert,T.K.,Zacarias-Cabeza,J.,Spicuglia,S.,de la Chapelle,A.L.,Heidemann,M.,Hintermair,C.,et al.(2011).Transcription initiation platforms and GTF recruitment at tissue-specific enhancers and promoters.Nat Struct Mol Biol 18,956-963.
Kowalczyk,M.S.,Hughes,J.R.,Garrick,D.,Lynch,M.D.,Sharpe,J.A.,Sloane-Stanley,J.A.,McGowan,S.J.,De Gobbi,M.,Hosseini,M.,Vernimmen,D.,et al.(2012).Intragenic enhancers act as alternative promoters.Mol Cell 45,447-458.
Lam,M.T.Y.,Li,W.,Rosenfeld,M.G.,and Glass,C.K.(2014).Enhancer RNAs and regulated transcriptional programs.Trends Biochem Sci 39,170-182.
Le Gras,S.,Keime,C.,Anthony,A.,Lotz,C.,De Longprez,L.,Brouillet,E.,Cassel,J.C.,Boutillier,A.L.,and Merienne,K.(2017).Altered enhancer transcription underlies Huntington’s disease striatal transcriptional signature.Sci Rep 7,42875.
Léveillé,N.,Melo,C.A.,Rooijers,K.,Díaz-Lagares,A.,Melo,S.A.,Korkmaz,G.,Lopes,R.,Akbari Moqadam,F.,Maia,A.R.,Wijchers,P.J.,et al.(2015).Genome-wide profiling of p53-regulated enhancer RNAs uncovers a subset of enhancers controlled by a lncRNA.Nat Commun 6,6520.
Levine,M.,Cattoglio,C.,and Tjian,R.(2014).Looping back to leap forward:transcription enters a new era.Cell 157,13-25.
Li,W.,Hu,Y.,Oh,S.,Ma,Q.,Merkurjev,D.,Song,X.,Zhou,X.,Liu,Z.,Tanasa,B.,He,X.,et al.(2015).Condensin I and II complexes license full estrogen receptorα-dependent enhancer activation.Mol Cell 59,188-202.
Li,W.,Notani,D.,Ma,Q.,Tanasa,B.,Nunez,E.,Chen,A.Y.,Merkurjev,D.,Zhang,J.,Ohgi,K.,Song,X.,et al.(2013).Functional roles of enhancer RNAs for oestrogen-dependent transcriptional activation.Nature 498,516-520.
Li,X.,Lu,C.,Lu,Q.,Li,C.,Zhu,J.,Zhao,T.,Chen,H.,and Jin H.(2019).Differentiated super-enhancers in lung cancer cells.Sci China Life Sci doi:10.1007/s11427-018-9319-4.
Liang,J.,Zhou,H.,Gerdt,C.,Tan,M.,Colson,T.,Kaye,K.M.,Kieff,E.,and Zhao,B.(2016).Epstein-Barr virus super-enhancer eRNAs are essential for MYC oncogene expression and lymphoblast proliferation.Proc Natl Acad Sci USA 113,14121-14126.
Liu,F.(2017).Enhancer-derived RNA:a primer.Genom Proteom Bioinf15,196-200.
Liu,Z.,Merkurjev,D.,Yang,F.,Li,W.,Oh,S.,Friedman,M.J.,Song,X.,Zhang,F.,Ma,Q.,Ohgi,K.A.,et al.(2014).Enhancer activation requires trans-recruitment of a mega transcription factor complex.Cell159,358-373.
Mansour,M.R.,Abraham,B.J.,Anders,L.,Berezovskaya,A.,Gutierrez,A.,Durbin,A.D.,Etchin,J.,Lawton,L.,Sallan,S.E.,Silverman,L.B.,et al.(2014).An oncogenic super-enhancer formed through somatic mutation of a noncoding intergenic element.Science 346,1373-1377.
Maruyama,A.,Mimura,J.,and Itoh,K.(2014).Non-coding RNA derived from the region adjacent to the human HO-1 E2 enhancer selectively regulates HO-1 gene induction by modulating Pol II binding.Nucl Acids Res 42,13599-13614.
Maurano,M.T.,Humbert,R.,Rynes,E.,Thurman,R.E.,Haugen,E.,Wang,H.,Reynolds,A.P.,Sandstrom,R.,Qu,H.,Brody,J.,et al.(2012).Systematic localization of common disease-associated variation in regulatory DNA.Science 337,1190-1195.
Melo,C.A.,Drost,J.,Wijchers,P.J.,van de Werken,H.,de Wit,E.,Oude Vrielink,J.A.F.,Elkon,R.,Melo,S.A.,Léveillé,N.,Kalluri,R.,et al.(2013).eRNAs are required for p53-dependent enhancer activity and gene transcription.Mol Cell 49,524-535.
Micheletti,R.,Plaisance,I.,Abraham,B.J.,Sarre,A.,Ting,C.C.,Alexanian,M.,Maric,D.,Maison,D.,Nemir,M.,Young,R.A.,et al.(2017).The long noncoding RNA Wisper controls cardiac fibrosis and remodeling.Sci Transl Med 9,eaai9118-295.
Mousavi,K.,Zare,H.,Dell’orso,S.,Grontved,L.,Gutierrez-Cruz,G.,Derfoul,A.,Hager,G.L.,and Sartorelli,V.(2013).eRNAs promote transcription by establishing chromatin accessibility at defined genomic loci.Mol Cell 51,606-617.
Natoli,G.,and Andrau,J.C.(2012).Noncoding transcription at enhancers:general principles and functional models.Annu Rev Genet 46,1-19.
Pennacchio,L.A.,Bickmore,W.,Dean,A.,Nobrega,M.A.,and Bejerano,G.(2013).Enhancers:five essential questions.Nat Rev Genet 14,288-295.
Plank,J.L.,and Dean,A.(2014).Enhancer function:mechanistic and genome-wide insights come together.Mol Cell 55,5-14.
Pnueli,L.,Rudnizky,S.,Yosefzon,Y.,and Melamed,P.(2015).RNAtranscribed from a distal enhancer is required for activating the chromatin at the promoter of the gonadotropinα-subunit gene.Proc Natl Acad Sci USA 112,4369-4374.
Pott,S.,and Lieb,J.D.(2015).What are super-enhancers?Nat Genet 47,8-12.
Puc,J.,Kozbial,P.,Li,W.,Tan,Y.,Liu,Z.,Suter,T.,Ohgi,K.A.,Zhang,J.,Aggarwal,A.K.,and Rosenfeld,M.G.(2015).Ligand-dependent enhancer activation regulated by topoisomerase-I activity.Cell 160,367-380.
Pulakanti,K.,Pinello,L.,Stelloh,C.,Blinka,S.,Allred,J.,Milanovich,S.,Kiblawi,S.,Peterson,J.,Wang,A.,Yuan,G.C.,et al.(2013).Enhancer transcribed RNAs arise from hypomethylated,Tet-occupied genomic regions.Epigenetics 8,1303-1320.
Rahman,S.,Zorca,C.E.,Traboulsi,T.,Noutahi,E.,Krause,M.R.,Mader,S.,and Zenklusen,D.(2017).Single-cell profiling reveals that eRNAaccumulation at enhancer-promoter loops is not required to sustain transcription.Nucl Acids Res 45,3017-3030.
Schaukowitch,K.,Joo,J.Y.,Liu,X.,Watts,J.K.,Martinez,C.,and Kim,T.K.(2014).Enhancer RNA facilitates NELF release from immediate early genes.Mol Cell 56,29-42.
Smith,E.,and Shilatifard,A.(2014).Enhancer biology and enhanceropathies.Nat Struct Mol Biol 21,210-219.
Wang,D.,Garcia-Bassets,I.,Benner,C.,Li,W.,Su,X.,Zhou,Y.,Qiu,J.,Liu,W.,Kaikkonen,M.U.,Ohgi,K.A.,et al.(2011).Reprogramming transcription by distinct classes of enhancers functionally defined by eRNA.Nature 474,390-394.
Whyte,W.A.,Orlando,D.A.,Hnisz,D.,Abraham,B.J.,Lin,C.Y.,Kagey,M.H.,Rahl,P.B.,Lee,T.I.,and Young,R.A.(2013).Master transcription factors and mediator establish super-enhancers at key cell identity genes.Cell 153,307-319.
Wu,H.,Nord,A.S.,Akiyama,J.A.,Shoukry,M.,Afzal,V.,Rubin,E.M.,Pennacchio,L.A.,and Visel,A.(2014).Tissue-specific RNAexpression marks distant-acting developmental enhancers.PLoSGenet 10,e1004610.
Yang,Y.,Su,Z.,Song,X.,Liang,B.,Zeng,F.,Chang,X.,and Huang,D.(2016).Enhancer RNA-driven looping enhances the transcription of the long noncoding RNA DHRS4-AS1,a controller of the DHRS4 gene cluster.Sci Rep 6,20961.
Yao,P.,Lin,P.,Gokoolparsadh,A.,Assareh,A.,Thang,M.W.C.,and Voineagu,I.(2015).Coexpression networks identify brain regionspecific enhancer RNAs in the human brain.Nat Neurosci 18,1168-1174.
Zabidi,M.A.,and Stark,A.(2016).Regulatory enhancer-core-promoter communication via transcription factors and cofactors.Trends Genets32,801-814.
Zhao,Y.,Wang,L.,Ren,S.,Wang,L.,Blackburn,P.R.,McNulty,M.S.,Gao,X.,Qiao,M.,Vessella,R.L.,Kohli,M.,et al.(2016).Activation of P-TEFb by androgen receptor-regulated enhancer RNAs in castrationresistant prostate cancer.Cell Rep 15,599-610.
Abraham,B.J.,Hnisz,D.,Weintraub,A.S.,Kwiatkowski,N.,Li,C.H.,Li,Z.,Weichert-Leahey,N.,Rahman,S.,Liu,Y.,Etchin,J.,et al.(2017).Small genomic insertions form enhancers that misregulate oncogenes.Nat Commun 8,14385.
Akhtar-Zaidi,B.,Cowper-Sal·lari,R.,Corradin,O.,Saiakhova,A.,Bartels,C.F.,Balasubramanian,D.,Myeroff,L.,Lutterbaugh,J.,Jarrar,A.,Kalady,M.F.,et al.(2012).Epigenomic enhancer profiling defines a signature of colon cancer.Science 336,736-739.
Allen,M.A.,Andrysik,Z.,Dengler,V.L.,Mellert,H.S.,Guarnieri,A.,Freeman,J.A.,Sullivan,K.D.,Galbraith,M.D.,Luo,X.,Kraus,W.L.,et al.(2014).Global analysis of p53-regulated transcription identifies its direct targets and unexpected regulatory mechanisms.eLife 3,e02200.
Alvarez-Dominguez,J.R.,Knoll,M.,Gromatzky,A.A.,and Lodish,H.F.(2017).The super-enhancer-derived alncRNA-EC7/bloodlinc potentiates red blood cell development in trans.Cell Rep 19,2503-2514.
Andersson,R.,Gebhard,C.,Miguel-Escalada,I.,Hoof,I.,Bornholdt,J.,Boyd,M.,Chen,Y.,Zhao,X.,Schmidl,C.,Suzuki,T.,et al.(2014).An atlas of active enhancers across human cell types and tissues.Nature507,455-461.
Arner,E.,Daub,C.O.,Vitting-Seerup,K.,Andersson,R.,Lilje,B.,Drabl?s,F.,Lennartsson,A.,R?nnerblad,M.,Hrydziuszko,O.,Vitezic,M.,et al.(2015).Transcribed enhancers lead waves of coordinated transcription in transitioning mammalian cells.Science 347,1010-1014.
Bales,D.J.(1990).On predicting the future of dentistry.Oper Dent 15,121.
Banerji,J.,Rusconi,S.,and Schaffner,W.(1981).Expression of aβ-globin gene is enhanced by remote SV40 DNA sequences.Cell 27,299-308.
Blackwood,E.M.,and Kadonaga,J.T.(1998).Going the distance:a current view of enhancer action.Science 281,60-63.
Chapuy,B.,McKeown,M.R.,Lin,C.Y.,Monti,S.,Roemer,M.G.M.,Qi,J.,Rahl,P.B.,Sun,H.H.,Yeda,K.T.,Doench,J.G.,et al.(2013).Discovery and characterization of super-enhancer-associated dependencies in diffuse large B cell lymphoma.Cancer Cell 24,777-790.
Cheng,H.,Dou,X.,and Han,J.D.J.(2016).Understanding superenhancers.Sci China Life Sci 59,277-280.
Cheng,J.H.,Pan,D.Z.C.,Tsai,Z.T.Y.,and Tsai,H.K.(2015).Genomewide analysis of enhancer RNA in gene regulation across 12 mouse tissues.Sci Rep 5,12648.
Chokas,A.L.,Bickford,J.S.,Barilovits,S.J.,Rogers,R.J.,Qiu,X.,Newsom,K.J.,Beachy,D.E.,and Nick,H.S.(2014).A TEAD1/p65complex regulates the eutherian-conserved MnSOD intronic enhancer,eRNA transcription and the innate immune response.Biochim Biophys Acta 1839,1205-1216.
Collis,P.,Antoniou,M.,and Grosveld,F.(1990).Definition of the minimal requirements within the human beta-globin gene and the dominant control region for high level expression..EMBO J 9,233-240.
Corradin,O.,Saiakhova,A.,Akhtar-Zaidi,B.,Myeroff,L.,Willis,J.,Cowper-Sal{middle dot}lari,R.,Lupien,M.,Markowitz,S.,and Scacheri,P.C.(2014).Combinatorial effects of multiple enhancer variants in linkage disequilibrium dictate levels of gene expression to confer susceptibility to common traits.Genome Res 24,1-13.
De Santa,F.,Barozzi,I.,Mietton,F.,Ghisletti,S.,Polletti,S.,Tusi,B.K.,Muller,H.,Ragoussis,J.,Wei,C.L.,and Natoli,G.(2010).A large fraction of extragenic RNA pol II transcription sites overlap enhancers.PLoS Biol 8,e1000384.
Djebali,S.,Davis,C.A.,Merkel,A.,Dobin,A.,Lassmann,T.,Mortazavi,A.,Tanzer,A.,Lagarde,J.,Lin,W.,Schlesinger,F.,et al.(2012).Landscape of transcription in human cells.Nature 489,101-108.
Dorighi,K.M.,Swigut,T.,Henriques,T.,Bhanu,N.V.,Scruggs,B.S.,Nady,N.,Still Ii,C.D.,Garcia,B.A.,Adelman,K.,and Wysocka,J.(2017).Mll3 and Mll4 facilitate enhancer RNA synthesis and transcription from promoters independently of H3K4 monomethylation.Mol Cell 66,568-576.e4.
Dukler,N.,Gulko,B.,Huang,Y.F.,and Siepel,A.(2017).Is a superenhancer greater than the sum of its parts?Nat Genet 49,2-3.
ENCODE Project Consortium.(2012).An integrated encyclopedia of DNAelements in the human genome.Nature 489,57-74.
Ernst,J.,Kheradpour,P.,Mikkelsen,T.S.,Shoresh,N.,Ward,L.D.,Epstein,C.B.,Zhang,X.,Wang,L.,Issner,R.,Coyne,M.,et al.(2011).Mapping and analysis of chromatin state dynamics in nine human cell types.Nature 473,43-49.
Feng,J.,Bi,C.,Clark,B.S.,Mady,R.,Shah,P.,and Kohtz,J.D.(2006).The Evf-2 noncoding RNA is transcribed from the Dlx-5/6ultraconserved region and functions as a Dlx-2 transcriptional coactivator.Genes Dev 20,1470-1484.
Flynn,R.A.,Do,B.T.,Rubin,A.J.,Calo,E.,Lee,B.,Kuchelmeister,H.,Rale,M.,Chu,C.,Kool,E.T.,Wysocka,J.,et al.(2016).7SK-BAF axis controls pervasive transcription at enhancers.Nat Struct Mol Biol 23,231-238.
Hah,N.,Benner,C.,Chong,L.W.,Yu,R.T.,Downes,M.,and Evans,R.M.(2015).Inflammation-sensitive super enhancers form domains of coordinately regulated enhancer RNAs.Proc Natl Acad Sci USA 112,E297-E302.
Hah,N.,Murakami,S.,Nagari,A.,Danko,C.G.,and Kraus,W.L.(2013).Enhancer transcripts mark active estrogen receptor binding sites.Genome Res 23,1210-1223.
Harris,H.(1959).Turnover of nuclear and cytoplasmic ribonucleic acid in two types of animal cell,with some further observations on the nucleolus.Biochem J 73,362-369.
He,H.,Li,W.,Wu,D.,Nagy,R.,Liyanarachchi,S.,Akagi,K.,Jendrzejewski,J.,Jiao,H.,Hoag,K.,Wen,B.,et al.(2013).Ultrarare mutation in long-range enhancer predisposes to thyroid carcinoma with high penetrance.PLoS ONE 8,e61920.
Heintzman,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.(2009).Histone modifications at human enhancers reflect global cell-typespecific gene expression.Nature 459,108-112.
Henley,C.M.Iii,Owings,M.H.,Stagner,B.B.,Martin,G.K.,and Lonsbury-Martin,B.L.(1990).Postnatal development of 2?1-?2otoacoustic emissions in pigmented rat.Hear Res 43,141-148.
Hsieh,C.L.,Fei,T.,Chen,Y.,Li,T.,Gao,Y.,Wang,X.,Sun,T.,Sweeney,C.J.,Lee,G.S.M.,Chen,S.,et al.(2014).Enhancer RNAs participate in androgen receptor-driven looping that selectively enhances gene activation.Proc Natl Acad Sci USA 111,7319-7324.
Isoda,T.,Moore,A.J.,He,Z.,Chandra,V.,Aida,M.,Denholtz,M.,Piet van Hamburg,J.,Fisch,K.M.,Chang,A.N.,Fahl,S.P.,et al.(2017).Non-coding transcription instructs chromatin folding and compartmentalization to dictate enhancer-promoter communication and T cell fate.Cell 171,103-119.e18.
Jeong,M.,and Goodell,M.A.Noncoding regulatory RNAs in hematopoiesis.(2016).Curr Top Dev Biol 118,245-270.
Kaikkonen,M.U.,Spann,N.J.,Heinz,S.,Romanoski,C.E.,Allison,K.A.,Stender,J.D.,Chun,H.B.,Tough,D.F.,Prinjha,R.K.,Benner,C.,et al.(2013).Remodeling of the enhancer landscape during macrophage activation is coupled to enhancer transcription.Mol Cell 51,310-325.
Kim,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.(2010).Widespread transcription at neuronal activity-regulated enhancers.Nature 465,182-187.
Koch,F.,Fenouil,R.,Gut,M.,Cauchy,P.,Albert,T.K.,Zacarias-Cabeza,J.,Spicuglia,S.,de la Chapelle,A.L.,Heidemann,M.,Hintermair,C.,et al.(2011).Transcription initiation platforms and GTF recruitment at tissue-specific enhancers and promoters.Nat Struct Mol Biol 18,956-963.
Kowalczyk,M.S.,Hughes,J.R.,Garrick,D.,Lynch,M.D.,Sharpe,J.A.,Sloane-Stanley,J.A.,McGowan,S.J.,De Gobbi,M.,Hosseini,M.,Vernimmen,D.,et al.(2012).Intragenic enhancers act as alternative promoters.Mol Cell 45,447-458.
Lam,M.T.Y.,Li,W.,Rosenfeld,M.G.,and Glass,C.K.(2014).Enhancer RNAs and regulated transcriptional programs.Trends Biochem Sci 39,170-182.
Le Gras,S.,Keime,C.,Anthony,A.,Lotz,C.,De Longprez,L.,Brouillet,E.,Cassel,J.C.,Boutillier,A.L.,and Merienne,K.(2017).Altered enhancer transcription underlies Huntington’s disease striatal transcriptional signature.Sci Rep 7,42875.
Léveillé,N.,Melo,C.A.,Rooijers,K.,Díaz-Lagares,A.,Melo,S.A.,Korkmaz,G.,Lopes,R.,Akbari Moqadam,F.,Maia,A.R.,Wijchers,P.J.,et al.(2015).Genome-wide profiling of p53-regulated enhancer RNAs uncovers a subset of enhancers controlled by a lncRNA.Nat Commun 6,6520.
Levine,M.,Cattoglio,C.,and Tjian,R.(2014).Looping back to leap forward:transcription enters a new era.Cell 157,13-25.
Li,W.,Hu,Y.,Oh,S.,Ma,Q.,Merkurjev,D.,Song,X.,Zhou,X.,Liu,Z.,Tanasa,B.,He,X.,et al.(2015).Condensin I and II complexes license full estrogen receptorα-dependent enhancer activation.Mol Cell 59,188-202.
Li,W.,Notani,D.,Ma,Q.,Tanasa,B.,Nunez,E.,Chen,A.Y.,Merkurjev,D.,Zhang,J.,Ohgi,K.,Song,X.,et al.(2013).Functional roles of enhancer RNAs for oestrogen-dependent transcriptional activation.Nature 498,516-520.
Li,X.,Lu,C.,Lu,Q.,Li,C.,Zhu,J.,Zhao,T.,Chen,H.,and Jin H.(2019).Differentiated super-enhancers in lung cancer cells.Sci China Life Sci doi:10.1007/s11427-018-9319-4.
Liang,J.,Zhou,H.,Gerdt,C.,Tan,M.,Colson,T.,Kaye,K.M.,Kieff,E.,and Zhao,B.(2016).Epstein-Barr virus super-enhancer eRNAs are essential for MYC oncogene expression and lymphoblast proliferation.Proc Natl Acad Sci USA 113,14121-14126.
Liu,F.(2017).Enhancer-derived RNA:a primer.Genom Proteom Bioinf15,196-200.
Liu,Z.,Merkurjev,D.,Yang,F.,Li,W.,Oh,S.,Friedman,M.J.,Song,X.,Zhang,F.,Ma,Q.,Ohgi,K.A.,et al.(2014).Enhancer activation requires trans-recruitment of a mega transcription factor complex.Cell159,358-373.
Mansour,M.R.,Abraham,B.J.,Anders,L.,Berezovskaya,A.,Gutierrez,A.,Durbin,A.D.,Etchin,J.,Lawton,L.,Sallan,S.E.,Silverman,L.B.,et al.(2014).An oncogenic super-enhancer formed through somatic mutation of a noncoding intergenic element.Science 346,1373-1377.
Maruyama,A.,Mimura,J.,and Itoh,K.(2014).Non-coding RNA derived from the region adjacent to the human HO-1 E2 enhancer selectively regulates HO-1 gene induction by modulating Pol II binding.Nucl Acids Res 42,13599-13614.
Maurano,M.T.,Humbert,R.,Rynes,E.,Thurman,R.E.,Haugen,E.,Wang,H.,Reynolds,A.P.,Sandstrom,R.,Qu,H.,Brody,J.,et al.(2012).Systematic localization of common disease-associated variation in regulatory DNA.Science 337,1190-1195.
Melo,C.A.,Drost,J.,Wijchers,P.J.,van de Werken,H.,de Wit,E.,Oude Vrielink,J.A.F.,Elkon,R.,Melo,S.A.,Léveillé,N.,Kalluri,R.,et al.(2013).eRNAs are required for p53-dependent enhancer activity and gene transcription.Mol Cell 49,524-535.
Micheletti,R.,Plaisance,I.,Abraham,B.J.,Sarre,A.,Ting,C.C.,Alexanian,M.,Maric,D.,Maison,D.,Nemir,M.,Young,R.A.,et al.(2017).The long noncoding RNA Wisper controls cardiac fibrosis and remodeling.Sci Transl Med 9,eaai9118-295.
Mousavi,K.,Zare,H.,Dell’orso,S.,Grontved,L.,Gutierrez-Cruz,G.,Derfoul,A.,Hager,G.L.,and Sartorelli,V.(2013).eRNAs promote transcription by establishing chromatin accessibility at defined genomic loci.Mol Cell 51,606-617.
Natoli,G.,and Andrau,J.C.(2012).Noncoding transcription at enhancers:general principles and functional models.Annu Rev Genet 46,1-19.
Pennacchio,L.A.,Bickmore,W.,Dean,A.,Nobrega,M.A.,and Bejerano,G.(2013).Enhancers:five essential questions.Nat Rev Genet 14,288-295.
Plank,J.L.,and Dean,A.(2014).Enhancer function:mechanistic and genome-wide insights come together.Mol Cell 55,5-14.
Pnueli,L.,Rudnizky,S.,Yosefzon,Y.,and Melamed,P.(2015).RNAtranscribed from a distal enhancer is required for activating the chromatin at the promoter of the gonadotropinα-subunit gene.Proc Natl Acad Sci USA 112,4369-4374.
Pott,S.,and Lieb,J.D.(2015).What are super-enhancers?Nat Genet 47,8-12.
Puc,J.,Kozbial,P.,Li,W.,Tan,Y.,Liu,Z.,Suter,T.,Ohgi,K.A.,Zhang,J.,Aggarwal,A.K.,and Rosenfeld,M.G.(2015).Ligand-dependent enhancer activation regulated by topoisomerase-I activity.Cell 160,367-380.
Pulakanti,K.,Pinello,L.,Stelloh,C.,Blinka,S.,Allred,J.,Milanovich,S.,Kiblawi,S.,Peterson,J.,Wang,A.,Yuan,G.C.,et al.(2013).Enhancer transcribed RNAs arise from hypomethylated,Tet-occupied genomic regions.Epigenetics 8,1303-1320.
Rahman,S.,Zorca,C.E.,Traboulsi,T.,Noutahi,E.,Krause,M.R.,Mader,S.,and Zenklusen,D.(2017).Single-cell profiling reveals that eRNAaccumulation at enhancer-promoter loops is not required to sustain transcription.Nucl Acids Res 45,3017-3030.
Schaukowitch,K.,Joo,J.Y.,Liu,X.,Watts,J.K.,Martinez,C.,and Kim,T.K.(2014).Enhancer RNA facilitates NELF release from immediate early genes.Mol Cell 56,29-42.
Smith,E.,and Shilatifard,A.(2014).Enhancer biology and enhanceropathies.Nat Struct Mol Biol 21,210-219.
Wang,D.,Garcia-Bassets,I.,Benner,C.,Li,W.,Su,X.,Zhou,Y.,Qiu,J.,Liu,W.,Kaikkonen,M.U.,Ohgi,K.A.,et al.(2011).Reprogramming transcription by distinct classes of enhancers functionally defined by eRNA.Nature 474,390-394.
Whyte,W.A.,Orlando,D.A.,Hnisz,D.,Abraham,B.J.,Lin,C.Y.,Kagey,M.H.,Rahl,P.B.,Lee,T.I.,and Young,R.A.(2013).Master transcription factors and mediator establish super-enhancers at key cell identity genes.Cell 153,307-319.
Wu,H.,Nord,A.S.,Akiyama,J.A.,Shoukry,M.,Afzal,V.,Rubin,E.M.,Pennacchio,L.A.,and Visel,A.(2014).Tissue-specific RNAexpression marks distant-acting developmental enhancers.PLoSGenet 10,e1004610.
Yang,Y.,Su,Z.,Song,X.,Liang,B.,Zeng,F.,Chang,X.,and Huang,D.(2016).Enhancer RNA-driven looping enhances the transcription of the long noncoding RNA DHRS4-AS1,a controller of the DHRS4 gene cluster.Sci Rep 6,20961.
Yao,P.,Lin,P.,Gokoolparsadh,A.,Assareh,A.,Thang,M.W.C.,and Voineagu,I.(2015).Coexpression networks identify brain regionspecific enhancer RNAs in the human brain.Nat Neurosci 18,1168-1174.
Zabidi,M.A.,and Stark,A.(2016).Regulatory enhancer-core-promoter communication via transcription factors and cofactors.Trends Genets32,801-814.
Zhao,Y.,Wang,L.,Ren,S.,Wang,L.,Blackburn,P.R.,McNulty,M.S.,Gao,X.,Qiao,M.,Vessella,R.L.,Kohli,M.,et al.(2016).Activation of P-TEFb by androgen receptor-regulated enhancer RNAs in castrationresistant prostate cancer.Cell Rep 15,599-610.