title: KLF3 regulates muscle-specific gene expression and synergizes with serum response factor on KLF binding sites.
abstract: This study identifies KLF3 as a transcriptional regulator of muscle genes and reveals a novel synergistic interaction between KLF3 and serum response factor (SRF). Using quantitative proteomics, KLF3 was identified as one of several candidate factors that recognize the MPEX control element in the Muscle creatine kinase (MCK) promoter. Chromatin immunoprecipitation analysis indicated that KLF3 is enriched at many muscle gene promoters (MCK, Myosin heavy chain IIa, Six4, Calcium channel receptor alpha-1, and Skeletal alpha-actin), and two KLF3 isoforms are upregulated during muscle differentiation. KLF3 and SRF physically associate and synergize in transactivating the MCK promoter independently of SRF binding to CArG motifs. The zinc finger and repression domains of KLF3 plus the MADS box and transcription activation domain of SRF are implicated in this synergy. Our results provide the first evidence of a role for KLF3 in muscle gene regulation and reveal an alternate mechanism for transcriptional regulation by SRF via its recruitment to KLF binding sites. Since both factors are expressed in all muscle lineages, SRF may regulate many striated- and smooth-muscle genes that lack known SRF control elements, thus further expanding the breadth of the emerging CArGome.
authors.affiliation: Department of Biochemistry, Box 357350, University of Washington, Seattle, WA 98195, USA.
authors.forename: Charis L
authors.initials: CL
authors.lastname: Himeda
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Ranish
authors.forename: Richard C M
authors.initials: RC
authors.lastname: Pearson
authors.forename: Merlin
authors.initials: M
authors.lastname: Crossley
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Hauschka
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics; D002454:Cell Differentiation; D002460:Cell Line; D052283:Creatine Kinase, MM Form / Q000235:genetics; D017931:DNA Primers / Q000235:genetics; D006801:Humans; D066298:In Vitro Techniques; D051741:Kruppel-Like Transcription Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008969:Molecular Sequence Data; D032448:Myoblasts, Skeletal / Q000166:cytology / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D054730:Protein Interaction Domains and Motifs; D040901:Proteomics; D026362:Serum Response Factor / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation
chemical_list: D017931:DNA Primers; C529780:Klf3 protein, mouse; D051741:Kruppel-Like Transcription Factors; D026362:Serum Response Factor; D052283:Creatine Kinase, MM Form
references.citation: Mol Cell Biol. 1993 Feb;13(2):1264-72
references.pmid: 8423791
references.citation: J Biol Chem. 1998 Jan 9;273(2):1026-31
references.pmid: 9422764
references.citation: Mol Cell Biol. 2004 Jun;24(12):5281-9
references.pmid: 15169892
references.citation: J Biol Chem. 2003 Nov 28;278(48):48004-11
references.pmid: 12970361
references.citation: Dev Cell. 2003 Jan;4(1):107-18
references.pmid: 12530967
references.citation: Mol Cell Biol. 2006 Sep;26(17):6664-74
references.pmid: 16914747
references.citation: Mol Cell Biol. 2002 Aug;22(15):5296-307
references.pmid: 12101226
references.citation: Mol Cell Biol. 2005 Feb;25(4):1549-59
references.pmid: 15684403
references.citation: Mol Cell Biol. 2000 Nov;20(22):8613-22
references.pmid: 11046156
references.citation: Bioessays. 2001 Aug;23(8):683-90
references.pmid: 11494316
references.citation: J Cell Biochem. 1998 Sep 1;70(3):366-75
references.pmid: 9706874
references.citation: Genes Dev. 2006 Jun 15;20(12):1545-56
references.pmid: 16778073
references.citation: Curr Opin Cell Biol. 2007 Dec;19(6):618-27
references.pmid: 18023168
references.citation: Proc Natl Acad Sci U S A. 2005 Jan 25;102(4):1082-7
references.pmid: 15647354
references.citation: J Biol Chem. 2001 Apr 27;276(17):14482-9
references.pmid: 11278942
references.citation: J Biol Chem. 2006 Jul 21;281(29):20383-92
references.pmid: 16690609
references.citation: Nat Protoc. 2006;1(1):179-85
references.pmid: 17406230
references.citation: Nucleic Acids Res. 2006 Jan 1;34(Database issue):D95-7
references.pmid: 16381983
references.citation: J Cell Biol. 1992 Sep;118(6):1489-500
references.pmid: 1522119
references.citation: Mol Cell Biol. 1996 Apr;16(4):1649-58
references.pmid: 8657140
references.citation: Anal Biochem. 1976 May 7;72:248-54
references.pmid: 942051
references.citation: Nucleic Acids Res. 1983 Mar 11;11(5):1475-89
references.pmid: 6828386
references.citation: J Biol Chem. 2003 Nov 21;278(47):46494-505
references.pmid: 12968024
references.citation: Genome Res. 2007 Feb;17(2):136-44
references.pmid: 17200232
references.citation: Mol Cell Biol. 2008 Oct;28(20):6521-35
references.pmid: 18710939
references.citation: Mol Cell Biol. 1993 May;13(5):2753-64
references.pmid: 8474439
references.citation: PLoS One. 2008;3(12):e3910
references.pmid: 19079548
references.citation: Mol Cell Biol. 1996 Sep;16(9):5058-68
references.pmid: 8756664
references.citation: Methods Cell Biol. 1997;52:85-116
references.pmid: 9379967
references.citation: J Biol Chem. 2003 Apr 11;278(15):12786-95
references.pmid: 12556451
references.citation: Mol Ther. 2007 Feb;15(2):320-9
references.pmid: 17235310
references.citation: Cell. 1993 Dec 31;75(7):1351-9
references.pmid: 8269513
references.citation: J Mol Cell Cardiol. 2007 Jul;43(1):1-10
references.pmid: 17531262
references.citation: J Biol Chem. 2002 Mar 1;277(9):7308-17
references.pmid: 11744740
references.citation: Mol Cell Biol. 1988 Jan;8(1):62-70
references.pmid: 3336366
references.citation: Cell. 1992 Oct 30;71(3):383-90
references.pmid: 1330322
references.citation: J Mol Cell Cardiol. 2003 Jun;35(6):577-93
references.pmid: 12788374
references.citation: Mol Cell Biol. 1996 Apr;16(4):1695-705
references.pmid: 8657145
references.citation: Circulation. 2005 Nov 8;112(19):2930-9
references.pmid: 16260633
references.citation: Mol Cell Biol. 2004 Mar;24(5):2132-43
references.pmid: 14966291
references.citation: Cell. 2002 Sep 20;110(6):725-35
references.pmid: 12297046
references.citation: Mol Cell Biol. 1993 Aug;13(8):4640-7
references.pmid: 8336707
references.citation: EMBO J. 1998 Sep 1;17(17):5129-40
references.pmid: 9724649
references.citation: Genome Res. 2006 Feb;16(2):197-207
references.pmid: 16365378
references.citation: J Cell Biol. 1987 Aug;105(2):949-56
references.pmid: 3624313
references.citation: Cell. 1995 Dec 29;83(7):1125-36
references.pmid: 8548800
references.citation: J Biol Chem. 1996 Mar 1;271(9):5258-64
references.pmid: 8617811
references.citation: J Mol Biol. 2001 Nov 30;314(3):495-506
references.pmid: 11846562
references.citation: J Cell Biochem. 2004 Sep 1;93(1):74-82
references.pmid: 15352164
references.citation: Dev Biol. 1996 Jul 10;177(1):250-64
references.pmid: 8660892
references.citation: Genomics. 1998 Jan 15;47(2):294-9
references.pmid: 9479502
references.citation: Mol Cell Biol. 1991 Oct;11(10):5090-100
references.pmid: 1922033
references.citation: Mol Cell Biol. 2008 Jun;28(12):3967-78
references.pmid: 18391014
references.citation: Cell. 2002 Sep 20;110(6):713-23
references.pmid: 12297045
references.citation: J Biol Chem. 2002 Jul 12;277(28):25775-82
references.pmid: 11983708
references.citation: J Biol Chem. 2001 Mar 30;276(13):10413-22
references.pmid: 11136726
references.citation: Nature. 1995 Feb 16;373(6515):632-5
references.pmid: 7854423
references.citation: Nature. 2004 Sep 23;431(7007):466-71
references.pmid: 15386014
references.citation: Bioessays. 2003 Jan;25(1):9-12
references.pmid: 12508276
references.citation: Int J Dev Biol. 1994 Dec;38(4):591-604
references.pmid: 7779681
references.citation: J Mol Cell Cardiol. 2003 Dec;35(12):1407-20
references.pmid: 14654367
references.citation: Proc Natl Acad Sci U S A. 2006 Mar 21;103(12):4516-21
references.pmid: 16537394
references.citation: Mol Cell Biol. 2003 Apr;23(7):2425-37
references.pmid: 12640126