title: Rho-actin signaling to the MRTF coactivators dominates the immediate transcriptional response to serum in fibroblasts.
abstract: The transcription factor SRF (serum response factor) recruits two families of coactivators, the MRTFs (myocardin-related transcription factors) and the TCFs (ternary complex factors), to couple gene transcription to growth factor signaling. Here we investigated the role of the SRF network in the immediate transcriptional response of fibroblasts to serum stimulation. SRF recruited its cofactors in a gene-specific manner, and virtually all MRTF binding was directed by SRF. Much of SRF DNA binding was serum-inducible, reflecting a requirement for MRTF-SRF complex formation in nucleosome displacement. We identified 960 serum-responsive SRF target genes, which were mostly MRTF-controlled, as assessed by MRTF chromatin immunoprecipitation (ChIP) combined with deep sequencing (ChIP-seq) and/or sensitivity to MRTF-linked signals. MRTF activation facilitates RNA polymerase II (Pol II) recruitment or promoter escape according to gene context. MRTF targets encode regulators of the cytoskeleton, transcription, and cell growth, underpinning the role of SRF in cytoskeletal dynamics and mechanosensing. Finally, we show that specific activation of either MRTFs or TCFs can reset the circadian clock.
authors.affiliation: Transcription Group.
authors.forename: Cyril
authors.initials: C
authors.lastname: Esnault
authors.forename: Aengus
authors.initials: A
authors.lastname: Stewart
authors.forename: Francesco
authors.initials: F
authors.lastname: Gualdrini
authors.forename: Phil
authors.initials: P
authors.lastname: East
authors.forename: Stuart
authors.initials: S
authors.lastname: Horswell
authors.forename: Nik
authors.initials: N
authors.lastname: Matthews
authors.forename: Richard
authors.initials: R
authors.lastname: Treisman
mesh_terms: D000199:Actins / Q000378:metabolism*; D000818:Animals; D056926:CLOCK Proteins / Q000235:genetics; D057906:Circadian Clocks / Q000235:genetics; D005347:Fibroblasts / Q000502:physiology*; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D056950:Period Circadian Proteins / Q000235:genetics / Q000378:metabolism; D044967:Serum / Q000378:metabolism*; D026362:Serum Response Factor / Q000378:metabolism; D015398:Signal Transduction; D014158:Transcription, Genetic / Q000235:genetics*
chemical_list: D000199:Actins; C539023:Per1 protein, mouse; D056950:Period Circadian Proteins; D026362:Serum Response Factor; D056926:CLOCK Proteins; D020928:Mitogen-Activated Protein Kinases
keywords: MRTF; Rho; SRF; TCF; chromatin; signal transduction
references.citation: Cell. 2010 Oct 1;143(1):156-69
references.pmid: 20887899
references.citation: Cell. 2012 Aug 17;150(4):780-91
references.pmid: 22863277
references.citation: Nat Protoc. 2009;4(1):44-57
references.pmid: 19131956
references.citation: Nature. 2013 May 23;497(7450):507-11
references.pmid: 23644458
references.citation: Cell. 2001 Jun 29;105(7):851-62
references.pmid: 11439182
references.citation: Nat Cell Biol. 2009 Mar;11(3):257-68
references.pmid: 19198601
references.citation: Nat Rev Cancer. 2012 Jul 19;12(8):540-52
references.pmid: 22810810
references.citation: Nature. 2004 Mar 11;428(6979):185-9
references.pmid: 15014501
references.citation: Genome Biol. 2008;9(9):R137
references.pmid: 18798982
references.citation: Nat Methods. 2008 Sep;5(9):829-34
references.pmid: 19160518
references.citation: J Biol Chem. 2001 Jul 6;276(27):24531-9
references.pmid: 11342553
references.citation: Development. 2010 Jul;137(14):2365-74
references.pmid: 20534669
references.citation: EMBO J. 1996 May 15;15(10):2496-507
references.pmid: 8665857
references.citation: Cell. 1998 Jun 12;93(6):929-37
references.pmid: 9635423
references.citation: Mol Cell Biol. 2011 Feb;31(4):861-75
references.pmid: 21135125
references.citation: Nature. 2007 Jun 14;447(7146):799-816
references.pmid: 17571346
references.citation: Science. 2012 Oct 19;338(6105):349-54
references.pmid: 22936566
references.citation: Annu Rev Biochem. 2011;80:437-71
references.pmid: 21548782
references.citation: Genes Dev. 2000 Mar 15;14(6):645-9
references.pmid: 10733524
references.citation: J Immunol. 2010 Jul 15;185(2):1082-92
references.pmid: 20554967
references.citation: Am J Pathol. 2008 Nov;173(5):1551-65
references.pmid: 18845837
references.citation: Nature. 2011 Jun 08;474(7350):179-83
references.pmid: 21654799
references.citation: Nat Cell Biol. 2002 Apr;4(4):294-301
references.pmid: 11912491
references.citation: Cell. 2003 Apr 18;113(2):147-58
references.pmid: 12705864
references.citation: Cell. 2003 May 2;113(3):329-42
references.pmid: 12732141
references.citation: Sci Signal. 2009 May 05;2(69):ra20
references.pmid: 19417216
references.citation: Nat Cell Biol. 2013 Jun;15(6):637-46
references.pmid: 23708000
references.citation: Nature. 2012 Sep 6;489(7414):75-82
references.pmid: 22955617
references.citation: J Biol Chem. 2006 Sep 1;281(35):25768-80
references.pmid: 16825190
references.citation: Mol Cell Biol. 1993 Aug;13(8):4640-7
references.pmid: 8336707
references.citation: J Cell Biol. 2007 Dec 3;179(5):1027-42
references.pmid: 18056415
references.citation: Genome Biol. 2010;11(10):R106
references.pmid: 20979621
references.citation: Nat Rev Mol Cell Biol. 2010 May;11(5):353-65
references.pmid: 20414257
references.citation: Mol Cell. 2010 May 28;38(4):576-89
references.pmid: 20513432
references.citation: Nat Neurosci. 1998 Dec;1(8):693-700
references.pmid: 10196585
references.citation: Am J Respir Cell Mol Biol. 2012 Sep;47(3):340-8
references.pmid: 22461426
references.citation: Science. 2013 Nov 8;342(6159):737-40
references.pmid: 24114784
references.citation: Nature. 1989 Jul 6;340(6228):68-70
references.pmid: 2786995
references.citation: Science. 2013 Aug 30;341(6149):1240104
references.pmid: 23990565
references.citation: Nat Rev Cancer. 2009 Feb;9(2):108-22
references.pmid: 19165226
references.citation: Genome Res. 2009 Nov;19(11):1963-73
references.pmid: 19687146
references.citation: Oncogene. 2009 Dec 10;28(49):4326-43
references.pmid: 19826415
references.citation: Cell. 2013 Jan 31;152(3):492-503
references.pmid: 23374345
references.citation: Science. 2009 Jun 26;324(5935):1673-7
references.pmid: 19556500
references.citation: Cancer Cell. 2005 Sep;8(3):241-54
references.pmid: 16169468
references.citation: Nature. 2010 May 13;465(7295):182-7
references.pmid: 20393465
references.citation: PLoS Biol. 2011 Apr;9(4):e1001046
references.pmid: 21526222
references.citation: Trends Cell Biol. 2006 Nov;16(11):588-96
references.pmid: 17035020
references.citation: J Cell Sci. 2011 Dec 15;124(Pt 24):4318-31
references.pmid: 22223881
references.citation: Cell. 2012 Oct 26;151(3):476-82
references.pmid: 23101621
references.citation: J Bone Miner Res. 2012 Aug;27(8):1659-68
references.pmid: 22434656
references.citation: Circ Res. 2005 Nov 11;97(10):983-91
references.pmid: 16224064
references.citation: Science. 2007 Jun 22;316(5832):1749-52
references.pmid: 17588931
references.citation: Mol Cell Biol. 2006 Jun;26(11):4134-48
references.pmid: 16705166