title: Discovery of active enhancers through bidirectional expression of short transcripts.
abstract: BACKGROUND
  Long-range regulatory elements, such as enhancers, exert substantial control over tissue-specific gene expression patterns. Genome-wide discovery of functional enhancers in different cell types is important for our understanding of genome function as well as human disease etiology.
  
  
  RESULTS
  In this study, we developed an in silico approach to model the previously reported phenomenon of transcriptional pausing, accompanied by divergent transcription, at active promoters. We then used this model for large-scale prediction of non-promoter-associated bidirectional expression of short transcripts. Our predictions were significantly enriched for DNase hypersensitive sites, histone H3 lysine 27 acetylation (H3K27ac), and other chromatin marks associated with active rather than poised or repressed enhancers. We also detected modest bidirectional expression at binding sites of the CCCTC-factor (CTCF) genome-wide, particularly those that overlap H3K27ac.
  
  
  CONCLUSIONS
  Our findings indicate that the signature of bidirectional expression of short transcripts, learned from promoter-proximal transcriptional pausing, can be used to predict active long-range regulatory elements genome-wide, likely due in part to specific association of RNA polymerase with enhancer regions.
authors.affiliation: Genome Technology Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Michael F
authors.initials: MF
authors.lastname: Melgar
authors.forename: Francis S
authors.initials: FS
authors.lastname: Collins
authors.forename: Praveen
authors.initials: P
authors.lastname: Sethupathy
mesh_terms: D000107:Acetylation; D000465:Algorithms; D001665:Binding Sites; D000076246:CCCTC-Binding Factor; D002843:Chromatin / Q000235:genetics; D003198:Computer Simulation; D012321:DNA-Directed RNA Polymerases / Q000235:genetics; D004742:Enhancer Elements, Genetic; D015870:Gene Expression; D015894:Genome, Human; D023281:Genomics; D006657:Histones / Q000235:genetics; D006801:Humans; D008957:Models, Genetic; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics*; D012097:Repressor Proteins / Q000235:genetics; D014158:Transcription, Genetic
chemical_list: D000076246:CCCTC-Binding Factor; C000619697:CTCF protein, human; D002843:Chromatin; D006657:Histones; D012333:RNA, Messenger; D012097:Repressor Proteins; D012321:DNA-Directed RNA Polymerases
references.citation: Nat Rev Genet. 2011 Apr;12(4):283-93
references.pmid: 21358745
references.citation: Cell. 1988 Sep 9;54(6):795-804
references.pmid: 3136931
references.citation: Proc Natl Acad Sci U S A. 2010 Dec 14;107(50):21931-6
references.pmid: 21106759
references.citation: Proc Natl Acad Sci U S A. 2009 Oct 27;106(43):18357-61
references.pmid: 19826084
references.citation: Nature. 2002 Apr 4;416(6880):499-506
references.pmid: 11932736
references.citation: Mol Cell. 2010 Nov 24;40(4):582-93
references.pmid: 21095588
references.citation: PLoS Biol. 2010 May 11;8(5):e1000384
references.pmid: 20485488
references.citation: Genome Res. 2011 Aug;21(8):1273-83
references.pmid: 21632746
references.citation: Genome Biol. 2008;9(9):R137
references.pmid: 18798982
references.citation: Science. 2010 Jan 15;327(5963):335-8
references.pmid: 20007866
references.citation: Cell. 2007 Mar 23;128(6):1231-45
references.pmid: 17382889
references.citation: Nat Rev Genet. 2008 Jan;9(1):38-48
references.pmid: 18071322
references.citation: Science. 2009 Jul 24;325(5939):429-32
references.pmid: 19628860
references.citation: Cell. 2009 Jun 26;137(7):1194-211
references.pmid: 19563753
references.citation: Mol Cell. 2010 Nov 24;40(4):571-81
references.pmid: 21095587
references.citation: Proc Natl Acad Sci U S A. 2009 Jun 9;106(23):9362-7
references.pmid: 19474294
references.citation: PLoS One. 2011 Jan 31;6(1):e16685
references.pmid: 21304912
references.citation: Curr Opin Genet Dev. 2011 Apr;21(2):231-5
references.pmid: 21324670
references.citation: Nature. 2007 Aug 2;448(7153):553-60
references.pmid: 17603471
references.citation: Science. 2008 Dec 19;322(5909):1845-8
references.pmid: 19056941
references.citation: Curr Opin Genet Dev. 2002 Apr;12(2):130-6
references.pmid: 11893484
references.citation: Mol Cell. 2010 Nov 24;40(4):507-8
references.pmid: 21095581
references.citation: Cell Metab. 2010 Nov 3;12(5):443-55
references.pmid: 21035756
references.citation: Cold Spring Harb Protoc. 2010 Feb;2010(2):pdb.prot5384
references.pmid: 20150147
references.citation: Nat Genet. 2007 Dec;39(12):1512-6
references.pmid: 17994019
references.citation: Nat Genet. 2007 Dec;39(12):1507-11
references.pmid: 17994021
references.citation: Nature. 2011 Feb 10;470(7333):279-83
references.pmid: 21160473
references.citation: Nature. 2005 Aug 11;436(7052):876-80
references.pmid: 15988478
references.citation: Cell. 2011 May 13;145(4):502-11
references.pmid: 21565610
references.citation: Cell. 2010 Nov 12;143(4):540-51
references.pmid: 21074046
references.citation: Cell. 2008 Jun 13;133(6):1106-17
references.pmid: 18555785
references.citation: Science. 2008 Dec 19;322(5909):1851-4
references.pmid: 19056938
references.citation: PLoS Genet. 2010 Apr 01;6(4):e1000895
references.pmid: 20369022
references.citation: Nature. 2011 May 5;473(7345):43-9
references.pmid: 21441907
references.citation: Transcription. 2011 Jan-Feb;2(1):9-14
references.pmid: 21326903
references.citation: Nature. 2011 May 15;474(7351):390-4
references.pmid: 21572438
references.citation: Nature. 2010 May 13;465(7295):182-7
references.pmid: 20393465
references.citation: Bioessays. 2010 Jan;32(1):37-50
references.pmid: 20020479
references.citation: Science. 2008 Dec 19;322(5909):1849-51
references.pmid: 19056940
references.citation: Nature. 2011 Jan 20;469(7330):368-73
references.pmid: 21248844
references.citation: Genome Res. 2009 Apr;19(4):590-601
references.pmid: 19251738
references.citation: Genes Dev. 2011 Apr 1;25(7):742-54
references.pmid: 21460038
references.citation: Mol Cell Biol. 2007 Mar;27(5):1631-48
references.pmid: 17210645
references.citation: FEBS Lett. 2005 Feb 7;579(4):909-15
references.pmid: 15680973
references.citation: PLoS Genet. 2010 Apr 01;6(4):e1000888
references.pmid: 20369019