title: Widespread transcription at neuronal activity-regulated enhancers.
abstract: We used genome-wide sequencing methods to study stimulus-dependent enhancer function in mouse cortical neurons. We identified approximately 12,000 neuronal activity-regulated enhancers that are bound by the general transcriptional co-activator CBP in an activity-dependent manner. A function of CBP at enhancers may be to recruit RNA polymerase II (RNAPII), as we also observed activity-regulated RNAPII binding to thousands of enhancers. Notably, RNAPII at enhancers transcribes bi-directionally a novel class of enhancer RNAs (eRNAs) within enhancer domains defined by the presence of histone H3 monomethylated at lysine 4. The level of eRNA expression at neuronal enhancers positively correlates with the level of messenger RNA synthesis at nearby genes, suggesting that eRNA synthesis occurs specifically at enhancers that are actively engaged in promoting mRNA synthesis. These findings reveal that a widespread mechanism of enhancer activation involves RNAPII binding and eRNA synthesis.
authors.affiliation: Department of Neurobiology, Harvard Medical School, 220 Longwood Avenue, Boston, Massachusetts 02115, USA.
authors.forename: Tae-Kyung
authors.initials: TK
authors.lastname: Kim
authors.forename: Martin
authors.initials: M
authors.lastname: Hemberg
authors.forename: Jesse M
authors.initials: JM
authors.lastname: Gray
authors.forename: Allen M
authors.initials: AM
authors.lastname: Costa
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Bear
authors.forename: Jing
authors.initials: J
authors.lastname: Wu
authors.forename: David A
authors.initials: DA
authors.lastname: Harmin
authors.forename: Mike
authors.initials: M
authors.lastname: Laptewicz
authors.forename: Kellie
authors.initials: K
authors.lastname: Barbara-Haley
authors.forename: Scott
authors.initials: S
authors.lastname: Kuersten
authors.forename: Eirene
authors.initials: E
authors.lastname: Markenscoff-Papadimitriou
authors.forename: Dietmar
authors.initials: D
authors.lastname: Kuhl
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Bito
authors.forename: Paul F
authors.initials: PF
authors.lastname: Worley
authors.forename: Gabriel
authors.initials: G
authors.lastname: Kreiman
authors.forename: Michael E
authors.initials: ME
authors.lastname: Greenberg
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics; D050882:CREB-Binding Protein / Q000378:metabolism; D016384:Consensus Sequence / Q000235:genetics; D003598:Cytoskeletal Proteins / Q000235:genetics; D004742:Enhancer Elements, Genetic / Q000235:genetics*; D005786:Gene Expression Regulation / Q000235:genetics*; D017930:Genes, Reporter; D016762:Genes, fos / Q000235:genetics; D006657:Histones / Q000378:metabolism; D008745:Methylation; D051379:Mice; D008810:Mice, Inbred C57BL; D009419:Nerve Tissue Proteins / Q000235:genetics; D009474:Neurons / Q000378:metabolism*; D012319:RNA Polymerase II / Q000378:metabolism; D022661:RNA, Untranslated / Q000096:biosynthesis / Q000235:genetics; D014158:Transcription, Genetic / Q000235:genetics*
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D050882:CREB-Binding Protein; D003598:Cytoskeletal Proteins; D006657:Histones; D009419:Nerve Tissue Proteins; D012319:RNA Polymerase II; D022661:RNA, Untranslated; C533005:Npas4 protein, mouse; C092069:activity regulated cytoskeletal-associated protein
references.citation: J Neurosci. 2001 Aug 1;21(15):5484-93
references.pmid: 11466419
references.citation: J Biol Chem. 2003 Jul 18;278(29):26303-6
references.pmid: 12764140
references.citation: J Neurosci. 2009 Feb 4;29(5):1525-37
references.pmid: 19193899
references.citation: Neuron. 2006 Nov 9;52(3):437-44
references.pmid: 17088210
references.citation: Nucleic Acids Res. 2004 Sep 15;32(16):4903-19
references.pmid: 15371553
references.citation: Neuron. 2006 Nov 9;52(3):475-84
references.pmid: 17088213
references.citation: Genome Biol. 2005;6(8):R64
references.pmid: 16086846
references.citation: Cell. 2007 May 18;129(4):823-37
references.pmid: 17512414
references.citation: Genome Res. 2008 Dec;18(12):1906-17
references.pmid: 18787082
references.citation: Nature. 2005 Aug 11;436(7052):876-80
references.pmid: 15988478
references.citation: Nature. 2009 May 7;459(7243):108-12
references.pmid: 19295514
references.citation: Nat Genet. 2007 Mar;39(3):311-8
references.pmid: 17277777
references.citation: Bioinformatics. 2008 Jul 1;24(13):i24-31
references.pmid: 18586720
references.citation: J Biol Chem. 2004 Dec 3;279(49):51704-13
references.pmid: 15465832
references.citation: PLoS Genet. 2007 Aug;3(8):e136
references.pmid: 17708682
references.citation: Nature. 2008 Oct 30;455(7217):1198-204
references.pmid: 18815592
references.citation: J Biol Chem. 1996 Feb 2;271(5):2373-5
references.pmid: 8576192
references.citation: Proc Natl Acad Sci U S A. 2009 Jan 6;106(1):316-21
references.pmid: 19116276
references.citation: Nat Rev Genet. 2009 Oct;10(10):669-80
references.pmid: 19736561
references.citation: Cell. 1981 Dec;27(2 Pt 1):299-308
references.pmid: 6277502
references.citation: Trends Biochem Sci. 2005 Nov;30(11):593-9
references.pmid: 16126390
references.citation: Trends Biochem Sci. 2008 Jun;33(6):265-73
references.pmid: 18467100
references.citation: Annu Rev Neurosci. 2008;31:563-90
references.pmid: 18558867
references.citation: Neuron. 2006 Nov 9;52(3):445-59
references.pmid: 17088211
references.citation: Nature. 2009 Feb 12;457(7231):854-8
references.pmid: 19212405
references.citation: Neuron. 2008 Sep 25;59(6):846-60
references.pmid: 18817726