KLF3 regulates muscle-specific gene expression and synergizes with serum response factor on KLF binding sites.
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.
Himeda
Charis L
CL
Department of Biochemistry, Box 357350, University of Washington, Seattle, WA 98195, USA.
Ranish
Jeffrey A
JA
Pearson
Richard C M
RC
Crossley
Merlin
M
Hauschka
Stephen D
SD
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
D017931:DNA Primers; C529780:Klf3 protein, mouse; D051741:Kruppel-Like Transcription Factors; D026362:Serum Response Factor; D052283:Creatine Kinase, MM Form
Mol Cell Biol. 1993 Feb;13(2):1264-72
8423791
J Biol Chem. 1998 Jan 9;273(2):1026-31
9422764
Mol Cell Biol. 2004 Jun;24(12):5281-9
15169892
J Biol Chem. 2003 Nov 28;278(48):48004-11
12970361
Dev Cell. 2003 Jan;4(1):107-18
12530967
Mol Cell Biol. 2006 Sep;26(17):6664-74
16914747
Mol Cell Biol. 2002 Aug;22(15):5296-307
12101226
Mol Cell Biol. 2005 Feb;25(4):1549-59
15684403
Mol Cell Biol. 2000 Nov;20(22):8613-22
11046156
Bioessays. 2001 Aug;23(8):683-90
11494316
J Cell Biochem. 1998 Sep 1;70(3):366-75
9706874
Genes Dev. 2006 Jun 15;20(12):1545-56
16778073
Curr Opin Cell Biol. 2007 Dec;19(6):618-27
18023168
Proc Natl Acad Sci U S A. 2005 Jan 25;102(4):1082-7
15647354
J Biol Chem. 2001 Apr 27;276(17):14482-9
11278942
J Biol Chem. 2006 Jul 21;281(29):20383-92
16690609
Nat Protoc. 2006;1(1):179-85
17406230
Nucleic Acids Res. 2006 Jan 1;34(Database issue):D95-7
16381983
J Cell Biol. 1992 Sep;118(6):1489-500
1522119
Mol Cell Biol. 1996 Apr;16(4):1649-58
8657140
Anal Biochem. 1976 May 7;72:248-54
942051
Nucleic Acids Res. 1983 Mar 11;11(5):1475-89
6828386
J Biol Chem. 2003 Nov 21;278(47):46494-505
12968024
Genome Res. 2007 Feb;17(2):136-44
17200232
Mol Cell Biol. 2008 Oct;28(20):6521-35
18710939
Mol Cell Biol. 1993 May;13(5):2753-64
8474439
PLoS One. 2008;3(12):e3910
19079548
Mol Cell Biol. 1996 Sep;16(9):5058-68
8756664
Methods Cell Biol. 1997;52:85-116
9379967
J Biol Chem. 2003 Apr 11;278(15):12786-95
12556451
Mol Ther. 2007 Feb;15(2):320-9
17235310
Cell. 1993 Dec 31;75(7):1351-9
8269513
J Mol Cell Cardiol. 2007 Jul;43(1):1-10
17531262
J Biol Chem. 2002 Mar 1;277(9):7308-17
11744740
Mol Cell Biol. 1988 Jan;8(1):62-70
3336366
Cell. 1992 Oct 30;71(3):383-90
1330322
J Mol Cell Cardiol. 2003 Jun;35(6):577-93
12788374
Mol Cell Biol. 1996 Apr;16(4):1695-705
8657145
Circulation. 2005 Nov 8;112(19):2930-9
16260633
Mol Cell Biol. 2004 Mar;24(5):2132-43
14966291
Cell. 2002 Sep 20;110(6):725-35
12297046
Mol Cell Biol. 1993 Aug;13(8):4640-7
8336707
EMBO J. 1998 Sep 1;17(17):5129-40
9724649
Genome Res. 2006 Feb;16(2):197-207
16365378
J Cell Biol. 1987 Aug;105(2):949-56
3624313
Cell. 1995 Dec 29;83(7):1125-36
8548800
J Biol Chem. 1996 Mar 1;271(9):5258-64
8617811
J Mol Biol. 2001 Nov 30;314(3):495-506
11846562
J Cell Biochem. 2004 Sep 1;93(1):74-82
15352164
Dev Biol. 1996 Jul 10;177(1):250-64
8660892
Genomics. 1998 Jan 15;47(2):294-9
9479502
Mol Cell Biol. 1991 Oct;11(10):5090-100
1922033
Mol Cell Biol. 2008 Jun;28(12):3967-78
18391014
Cell. 2002 Sep 20;110(6):713-23
12297045
J Biol Chem. 2002 Jul 12;277(28):25775-82
11983708
J Biol Chem. 2001 Mar 30;276(13):10413-22
11136726
Nature. 1995 Feb 16;373(6515):632-5
7854423
Nature. 2004 Sep 23;431(7007):466-71
15386014
Bioessays. 2003 Jan;25(1):9-12
12508276
Int J Dev Biol. 1994 Dec;38(4):591-604
7779681
J Mol Cell Cardiol. 2003 Dec;35(12):1407-20
14654367
Proc Natl Acad Sci U S A. 2006 Mar 21;103(12):4516-21
16537394
Mol Cell Biol. 2003 Apr;23(7):2425-37
12640126