PC4 coactivates MyoD by relieving the histone deacetylase 4-mediated inhibition of myocyte enhancer factor 2C.
Histone deacetylase 4 (HDAC4) negatively regulates skeletal myogenesis by associating with the myocyte enhancer factor 2 (MEF2) transcription factors. Our data indicate that the gene PC4 (interferon-related developmental regulator 1 [IFRD1], Tis7), which we have previously shown to be required for myoblast differentiation, is both induced by MyoD and potentiates the transcriptional activity of MyoD, thus revealing a positive regulatory loop between these molecules. Enhancement by PC4 of MyoD-dependent activation of muscle gene promoters occurs selectively through MEF2 binding sites. Furthermore, PC4 localizes in the nucleus of differentiating myoblasts, associates with MEF2C, and is able to counteract the HDAC4-mediated inhibition of MEF2C. This latter action can be explained by the observed ability of PC4 to dose dependently displace HDAC4 from MEF2C. Consistently, we have observed that (i) the region of PC4 that binds MEF2C is sufficient to counteract the inhibition by HDAC4; (ii) PC4, although able to bind HDAC4, does not inhibit the enzymatic activity of HDAC4; and (iii) PC4 overcomes the inhibition mediated by the amino-terminal domain of HDAC4, which associates with MEF2C but not with PC4. Together, our findings strongly suggest that PC4 acts as a coactivator of MyoD and MEF2C by removing the inhibitory effect of HDAC4, thus exerting a pivotal function during myogenesis.
Micheli
Laura
L
Istituto di Neurobiologia e Medicina Molecolare, Consiglio Nazionale delle Ricerche, Viale Marx 15, 00137, Rome, Italy.
Leonardi
Luca
L
Conti
Filippo
F
Buanne
Pasquale
P
Canu
Nadia
N
Caruso
Maurizia
M
Tirone
Felice
F
D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology; D002467:Cell Nucleus / Q000737:chemistry; D002478:Cells, Cultured; D018507:Gene Expression Regulation, Developmental; D006655:Histone Deacetylases / Q000378:metabolism / Q000502:physiology*; D017874:Immediate-Early Proteins / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D064326:MEF2 Transcription Factors; D008565:Membrane Proteins / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008969:Molecular Sequence Data; D024510:Muscle Development / Q000235:genetics / Q000502:physiology*; D017570:MyoD Protein / Q000235:genetics / Q000378:metabolism*; D032446:Myoblasts / Q000737:chemistry / Q000166:cytology / Q000502:physiology; D018006:Myogenic Regulatory Factors / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017384:Sequence Deletion; D014158:Transcription, Genetic / Q000235:genetics / Q000502:physiology; D020798:Two-Hybrid System Techniques; D015854:Up-Regulation
C084979:Ifrd1 protein, rat; D017874:Immediate-Early Proteins; D064326:MEF2 Transcription Factors; C578041:Mef2c protein, mouse; D008565:Membrane Proteins; D017570:MyoD Protein; D018006:Myogenic Regulatory Factors; C498618:Hdac5 protein, mouse; C498619:Hdac5 protein, rat; D006655:Histone Deacetylases
J Biol Chem. 2001 May 18;276(20):17007-13
11279209
Nucleic Acids Res. 2001 Aug 15;29(16):3439-47
11504882
Curr Opin Genet Dev. 2001 Oct;11(5):497-504
11532390
J Biol Chem. 2001 Sep 14;276(37):35042-8
11470791
Mol Cell. 2001 Oct;8(4):885-97
11684023
Mol Cell. 2002 Jan;9(1):45-57
11804585
EMBO J. 2002 Sep 2;21(17):4621-31
12198164
Mol Cell Biol. 2002 Oct;22(20):7302-12
12242305
J Anat. 2003 Jan;202(1):59-68
12587921
Mol Cell Biol. 2003 Apr;23(8):2893-906
12665587
Mol Cell Neurosci. 2003 Mar;22(3):353-64
12691737
J Biol Chem. 2003 Jun 27;278(26):23515-21
12709441
Mol Cell Biol. 2004 Apr;24(8):3514-25
15060170
J Mol Biol. 2004 Feb 20;336(3):589-95
15095974
Anal Biochem. 1976 May 7;72:248-54
942051
Nature. 1977 Dec 22-29;270(5639):725-7
563524
Proc Natl Acad Sci U S A. 1977 Dec;74(12):5463-7
271968
Mol Cell Biol. 1982 Sep;2(9):1044-51
6960240
Cell. 1993 Dec 31;75(7):1351-9
8269513
Mol Cell Biol. 1994 Mar;14(3):1647-56
8114702
J Neurosci Res. 1994 Apr 1;37(5):660-74
8028043
Curr Opin Cell Biol. 1994 Jun;6(3):432-42
7917336
Oncogene. 1994 Dec;9(12):3579-90
7970718
Science. 1995 Feb 3;267(5198):688-93
7839146
Cell. 1987 Dec 24;51(6):987-1000
3690668
Genes Dev. 1995 Mar 15;9(6):730-41
7729689
Cell Growth Differ. 1995 Feb;6(2):159-69
7756174
EMBO J. 1995 Aug 1;14(15):3679-86
7641687
J Neurosci. 1995 Aug;15(8):5727-38
7643214
FASEB J. 1995 Dec;9(15):1595-604
8529839
Cell. 1995 Dec 29;83(7):1125-36
8548800
Cell. 1996 Apr 5;85(1):1-4
8620528
Genes Dev. 1996 May 15;10(10):1173-83
8675005
Mol Cell Biol. 1996 Jun;16(6):2627-36
8649370
Curr Opin Genet Dev. 1996 Aug;6(4):445-53
8791524
Brain Res. 1996 Jan 29;707(2):293-7
8919308
Mol Cell Biol. 1997 Feb;17(2):1010-26
9001254
DNA Cell Biol. 1997 Apr;16(4):433-42
9150430
Science. 1997 May 30;276(5317):1404-7
9162005
Mol Cell Biol. 1998 Jan;18(1):69-77
9418854
Mol Cell. 1997 Dec;1(1):35-45
9659901
Genomics. 1998 Jul 15;51(2):233-42
9722946
Annu Rev Biochem. 1998;67:545-79
9759497
Annu Rev Cell Dev Biol. 1998;14:167-96
9891782
J Biol Chem. 1999 Apr 23;274(17):11713-20
10206986
Development. 1999 May;126(10):2045-52
10207130
Proc Natl Acad Sci U S A. 1999 Apr 27;96(9):4868-73
10220385
Mol Cell Biol. 1999 Jul;19(7):5203-17
10373569
EMBO J. 1999 Sep 15;18(18):5099-107
10487761
Mol Cell Biol. 1999 Nov;19(11):7816-27
10523670
Anal Biochem. 1983 Jul 1;132(1):6-13
6312838
Methods Enzymol. 1987;152:704-20
2889129
Cell. 1989 Feb 24;56(4):607-17
2537150
Cell. 1989 Mar 10;56(5):777-83
2493990
Proc Natl Acad Sci U S A. 1989 Mar;86(6):2088-92
2467301
EMBO J. 1989 Mar;8(3):701-9
2721498
Genes Dev. 1989 May;3(5):628-40
2473006
Cell. 1989 Sep 8;58(5):823-31
2550138
Oncogene. 1989 Oct;4(10):1263-5
2797820
Mol Cell Biol. 1989 Nov;9(11):5022-33
2601707
Proc Natl Acad Sci U S A. 1990 Feb;87(3):1089-93
2300571
EMBO J. 1990 Mar;9(3):821-31
2311584
Genes Dev. 1989 Dec;3(12B):2050-61
2560751
Gene. 1990 May 14;89(2):211-21
2165020
Proc Natl Acad Sci U S A. 1990 Aug;87(15):5623-7
2377600
Science. 1990 Nov 23;250(4984):1104-10
2174572
Science. 1991 Feb 15;251(4995):761-6
1846704
Mol Cell Biol. 1991 Aug;11(8):4104-10
1649388
Cell. 1991 Jul 26;66(2):305-15
1649701
Mol Cell Biol. 1991 Oct;11(10):4854-62
1656214
Mol Cell Biol. 1992 Sep;12(9):3665-77
1324403
Genes Dev. 1992 Sep;6(9):1783-98
1516833
Cancer Res. 1992 Dec 1;52(23):6431-9
1384962
J Biol Chem. 1993 Jan 5;268(1):5-8
8380166
Mol Cell Biol. 1993 Apr;13(4):2564-77
8455629
Mol Cell Biol. 1993 May;13(5):2753-64
8474439
Proc Natl Acad Sci U S A. 1993 Jun 1;90(11):5282-6
8506376
Genes Dev. 1993 Jul;7(7A):1277-89
8391506
Nature. 1993 Aug 5;364(6437):501-6
8393145
Nature. 1993 Aug 5;364(6437):532-5
8393146
Cell. 1993 Dec 31;75(7):1241-4
8269506
Genes Dev. 2000 Jan 1;14(1):45-54
10640275
Mol Cell Biol. 2000 Mar;20(5):1797-815
10669755
Proc Natl Acad Sci U S A. 2000 Apr 11;97(8):4070-5
10737771
J Biol Chem. 2000 May 19;275(20):15594-9
10748098
Mol Cell. 2000 Aug;6(2):233-44
10983972
Nature. 2000 Nov 2;408(6808):106-11
11081517
J Biol Chem. 2001 Jan 5;276(1):35-9
11022042
EMBO J. 2001 Apr 2;20(7):1739-53
11285237