Control of Cardiac-specific Transcription by p300 through Myocyte Enhancer Factor-2D (2001)

The transcriptional integrator p300 regulates gene expression by interaction with sequence-specific DNA-binding proteins and local remodeling of chromatin. p300 is required for cardiac-specific gene transcription, but the molecular basis of this requirement is unknown. Here we report that the MADS (MCM-1, agamous, deficiens, serum response factor) box transcription factor myocyte enhancer factor-2D (MEF-2D) acts as the principal conduit for cardiac transcriptional activation by p300. p300 activation of the native 2130-base pair human skeletal α-actin promoter required a single hybrid MEF-2/GATA-4 DNA motif centered at −1256 base pairs. Maximal expression of the promoter in cultured myocytes and in vivo correlated with binding of both MEF-2 and p300, but not GATA-4, to this AT-rich motif. p300 and MEF-2 were coprecipitated from cardiac nuclear extracts by an oligomer containing this element. p300 was found exclusively in a complex with MEF-2D at this and related sites in other cardiac-restricted promoters. MEF-2D, but not other MEFs, significantly potentiated cardiac-specific transcription by p300. No physical or functional interaction was observed between p300 and other factors implicated in skeletal actin transcription, including GATA-4, TEF-1, or SRF. These results show that, in the intact cell, p300 interactions with its protein targets are highly selective and that MEF-2D is the preferred channel for p300-mediated transcriptional control in the heart.AF288779 The transcriptional integrator p300 regulates gene expression by interaction with sequence-specific DNA-binding proteins and local remodeling of chromatin. p300 is required for cardiac-specific gene transcription, but the molecular basis of this requirement is unknown. Here we report that the MADS (MCM-1, agamous, deficiens, serum response factor) box transcription factor myocyte enhancer factor-2D (MEF-2D) acts as the principal conduit for cardiac transcriptional activation by p300. p300 activation of the native 2130-base pair human skeletal α-actin promoter required a single hybrid MEF-2/GATA-4 DNA motif centered at −1256 base pairs. Maximal expression of the promoter in cultured myocytes and in vivo correlated with binding of both MEF-2 and p300, but not GATA-4, to this AT-rich motif. p300 and MEF-2 were coprecipitated from cardiac nuclear extracts by an oligomer containing this element. p300 was found exclusively in a complex with MEF-2D at this and related sites in other cardiac-restricted promoters. MEF-2D, but not other MEFs, significantly potentiated cardiac-specific transcription by p300. No physical or functional interaction was observed between p300 and other factors implicated in skeletal actin transcription, including GATA-4, TEF-1, or SRF. These results show that, in the intact cell, p300 interactions with its protein targets are highly selective and that MEF-2D is the preferred channel for p300-mediated transcriptional control in the heart.AF288779 cAMP-responsive element binding protein-binding protein myocyte enhancer factor base pair(s) minimal essential medium minimal essential medium supplemented with insulin, transferrin, vitamin B12, penicillin, and streptomycin minimal essential medium with Eagle's salts, penicillin, streptomycin, and 5% fetal bovine serum α-myosin heavy chain human skeletal actin polymerase chain reaction electrophoretic mobility shift assay serum response element MCM-1, agamous, deficiens, serum response factor Transcriptional coactivators, or integrators, are members of a class of transcription factors that bring about tissue- and stimulus-specific changes in gene expression by coordinating groups of signal responsive proteins in the cell. Coactivators do not bind independently to DNA, but are thought to stabilize the formation of specific transcription factor-DNA complexes and to cause the local unwinding of chromatin directly or by recruitment of histone-remodeling enzymes (1Struhl K. Genes Dev. 1998; 12: 599-606Crossref PubMed Scopus (1530) Google Scholar, 2Lee D.Y. Hayes J.J. Pruss D. Wolffe A.P. Cell. 1993; 72: 73-84Abstract Full Text PDF PubMed Scopus (952) Google Scholar). Specific coactivator families have been identified for regulation of steroid hormone-responsive genes (SRC-1, SRC-3) (3Yao T.P. Ku G. Zhou N. Scully R. Livingston D.M. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: 10626-10631Crossref PubMed Scopus (392) Google Scholar, 4Xu J. Liao L. Ning G. Yoshida-Komiya H. Deng C. O'Malley B.W. Proc. Natl. Acad. Sci. U. S. A. 2000; 97: 6379-6384Crossref PubMed Scopus (451) Google Scholar, 5Leo C. Chen J.D. Gene ( Amst .). 2000; 245: 1-11Crossref PubMed Scopus (434) Google Scholar) and fatty acid regulatory proteins (PGC-1) (6Lowell B.B. Spiegelman B.M. Nature. 2000; 404: 652-660Crossref PubMed Scopus (1267) Google Scholar, 7Vega R.B. Huss J.M. Kelly D.P. Mol. Cell. Biol. 2000; 20: 1868-1876Crossref PubMed Scopus (913) Google Scholar). Gene targeting experiments have confirmed that the activities of these coactivatorsin vivo are highly tissue-restricted, although the molecular basis of this specificity is not well understood (4Xu J. Liao L. Ning G. Yoshida-Komiya H. Deng C. O'Malley B.W. Proc. Natl. Acad. Sci. U. S. A. 2000; 97: 6379-6384Crossref PubMed Scopus (451) Google Scholar, 6Lowell B.B. Spiegelman B.M. Nature. 2000; 404: 652-660Crossref PubMed Scopus (1267) Google Scholar, 8Tanaka Y. Naruse I. Maekawa T. Masuya H. Shiroishi T. Ishii S. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 10215-10220Crossref PubMed Scopus (256) Google Scholar, 9Kawasaki H. Eckner R. Yao T.P. Taira K. Chiu R. Livingston D.M. Yokoyama K.K. Nature. 1998; 393: 284-289Crossref PubMed Scopus (301) Google Scholar, 10Yao T.P. Oh S.P. Fuchs M. Zhou N.D. Ch'ng L.E. Newsome D. Bronson R.T. Li E. Livingston D.M. Eckner R. Cell. 1998; 93: 361-372Abstract Full Text Full Text PDF PubMed Scopus (810) Google Scholar). An important subgroup of coactivators is represented by the closely related transcriptional integrators p300 and cAMP-responsive element binding protein-binding protein (CBP).1 These large proteins share extensive sequence homology and many structural features and appear to have arisen as part of an ancestral gene duplication (11Giles R.H. Dauwerse H.G. van Ommen G.J. Breuning M.H. Am. J. Hum. Genet. 1998; 63: 1240-1242Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar, 12Arany Z. Sellers W.R. Livingston D.M. Eckner R. Cell. 1997; 77: 799-800Abstract Full Text PDF Scopus (370) Google Scholar, 13Giordano A. Avantaggiati M.L. J. Cell. Physiol. 1999; 181: 218-230Crossref PubMed Scopus (252) Google Scholar). The cellular levels and activities of p300 and CBP are tightly regulated through steroid, adrenergic, and growth factor signals as well as during the cell cycle (14Snowden A.W. Perkins N.D. Biochem. Pharmacol. 1998; 55: 1947-1954Crossref PubMed Scopus (55) Google Scholar). Critical roles for p300 and CBP have been identified in growth, differentiation, apoptosis, and tissue-specific gene expression, reflecting their interaction with multiple cellular regulatory proteins (13Giordano A. Avantaggiati M.L. J. Cell. Physiol. 1999; 181: 218-230Crossref PubMed Scopus (252) Google Scholar). A particular requirement for p300 is observed in the heart. Mice deficient in p300 have an embryonic lethal phenotype characterized by failure of cardiac myocyte proliferation and muscle-specific gene expression (10Yao T.P. Oh S.P. Fuchs M. Zhou N.D. Ch'ng L.E. Newsome D. Bronson R.T. Li E. Livingston D.M. Eckner R. Cell. 1998; 93: 361-372Abstract Full Text Full Text PDF PubMed Scopus (810) Google Scholar). In the postnatal heart, adenovirus E1A selectively inhibits cardiac muscle-specific gene expression by binding to p300 and/or related proteins (15Bishopric N.H. Zeng G.-Q. Sato B. Webster K.A. J. Biol. Chem. 1997; 272: 20584-20594Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar, 16Kirshenbaum L.A. Schneider M.D. J. Biol. Chem. 1995; 270: 7791-7794Abstract Full Text Full Text PDF PubMed Scopus (138) Google Scholar, 17Hasegawa K. Meyers M.B. Kitsis R.N. J. Biol. Chem. 1997; 272: 20049-20054Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar). Although p300 is also required for skeletal muscle gene transcription by the tissue-specific basic helix-loop helix protein MyoD, the heart lacks to this transcription factor J. Y. L. Mol. Cell. Biol. 1997; PubMed Scopus Google Scholar). The molecular and of p300-mediated transcriptional regulation in the heart are not of the human skeletal α-actin gene is tightly to In the skeletal actin is of a of genes in response to as in and during the response to growth and other in cell N.H. L. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar, N.H. Webster K.A. J. Biol. Chem. Full Text PDF PubMed Google Scholar, S. B. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar, Schneider M.D. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar). Although skeletal actin is the actin in the human heart, is during L. D. M. K. J. PubMed Scopus Google Scholar, S. H. M. M. M. Sci. 1998; 63: PubMed Scopus Google Scholar, M. M. H. T. S. K. J. Am. 1995; PubMed Scopus Google Scholar) and is an important of in the N.H. Webster K.A. J. Biol. Chem. Full Text PDF PubMed Google Scholar, W.R. Schneider M.D. J. Biol. Chem. Full Text PDF PubMed Google Scholar, K. J. Biol. Chem. 1995; 270: Full Text Full Text PDF PubMed Scopus Google Scholar, W.R. Schneider M.D. J. Biol. Chem. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar, A. J. Mol. 1998; PubMed Scopus Google Scholar). of skeletal actin expression in the heart both and cardiac-specific transcription the have not been The human skeletal actin promoter transcriptional activation to and to are required for tissue-specific expression in both skeletal and cardiac myocytes N.H. L. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar). The promoter functional binding sites for and A. L. PubMed Scopus Google Scholar). we report the sequence of the human skeletal actin and that DNA motif the transcriptional is of the p300 activation centered at the MADS (MCM-1, agamous, deficiens, serum response factor) box transcription factor MEF-2 as well as GATA-4, and is required for expression in both and cardiac The motif also cardiac nuclear p300, and activation of the promoter by p300 and activation not interaction with GATA-4, or TEF-1, that p300 selectively targets MEF-2 in the of a native these and interactions between MEF-2 and C. E. J. T. J. 1999; PubMed Scopus Google we that MEF-2 expression of the cardiac phenotype by as a channel for chromatin remodeling cardiac-specific promoters. were by A p300 expression was the of R. GATA-4, and p300 were from The p300 was by and enzymes were from other molecular were from as and were of the The promoter sequence was by DNA an DNA in the of The was to skeletal actin A containing the promoter and to the of transcription, including of was in the of and were by and/or as J. T. A Scholar). the of in this and the specific for of are in I. are in the of gene to the transcription a of with the sequence by S. H. L. Gene Google Scholar) as through the in sequence are through for in a and of the promoter were by of the at sites at and and or to sites in the The was by at the and the and was by at the and of the to the with and with a of in the The was by with and of the and of to and sites was as 1997; PubMed Scopus Google Scholar) with were DNA with the at the of were DNA polymerase was to of DNA and The with the was from and to in the promoter were by of containing in a or to the box by and sites at the and The was and to was this to and were by and to the of were with a of and were a with of and with a of and in a The was by a and the for DNA DNA was directly the of the in a of control and of in was for at the with were with a lethal of and the heart for of gene in extracts were as H. T. T. L. Li Y. L. J. Mol. Full Text PDF PubMed Scopus Google Scholar). and promoter to were as and were from were in with of or in with the were in with Eagle's salts, penicillin, streptomycin, and fetal bovine were as N.H. L. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar) by and a of and at a of were for by for to the of to and during were in with Eagle's salts, penicillin, streptomycin, and 5% fetal bovine serum were in a medium of supplemented with insulin, transferrin, vitamin B12, penicillin, and streptomycin were in 5% at and as myocytes were with and other the an of the Mol. Cell. Biol. PubMed Scopus Google Scholar). of myocytes were with of and of p300 expression of MEF-2 expression or an of expression were with and in that medium for an were with and in and were at a of also the were and during in or supplemented with fetal bovine penicillin, and the were with and for as A was to in cell of nuclear cardiac myocytes were in and cultured in for to for extracts were as J.D. R. PubMed Scopus Google that the was a of by were the protein assay of nuclear were and at shift containing the and and were as in were and with and mobility shift were as Mol. Cell. Biol. 12: PubMed Scopus Google Scholar) In of were to binding that of nuclear protein in of a containing were for at and a 5% at were with the binding for at of the of sequence-specific a of was the No interaction was observed in the of nuclear protein not in muscle muscle in a of nuclear from cardiac myocytes as was in with of MEF-2 or p300 was were for at with was to the and were for an at the of the were and the was to were with in of and for of the nuclear and were also with and protein were or of MEF-2 were to a cell were with MEF-2 p300 and p300 complexes were by A containing the motif was to the at a of and to as Mol. Cell. Biol. 1998; PubMed Scopus Google Scholar). of MEF-2 and p300, the were with containing bovine serum and with a containing The were with of and at in with and binding 5% were to and to the with the binding myocyte nuclear was with binding for at and with the for proteins were from the with containing and of were for proteins to the were with binding containing were by for p300 and for and by to p300 and MEF-2 as not bind DNA but is to specific gene control by transcription factors that bind to these we for binding sites for DNA-binding transcription factors in the promoter that or of The human skeletal actin promoter binding sites for TEF-1, and to the and skeletal actin S. H.G. E. 1993; Google Scholar, H. T. T. L. Li Y. L. J. Mol. Full Text PDF PubMed Scopus Google Scholar, and J.D. Mol. Cell. Biol. PubMed Google Scholar, and regulatory have been to the promoter to N.H. L. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar). these we the human skeletal actin promoter from to not this sequence are DNA binding sites at and as well as not A AT-rich motif was found centered at −1256 S. H. L. Gene Google Scholar) A AT-rich by from the binding for MEF-2 J.D. Cell. 1995; Full Text PDF PubMed Scopus Google Scholar). also for binding sites by of the promoter with the binding from the promoter binding of with the MEF-2 the binding motif was An was centered at A and and the functional of these the promoter was to and and The were for in by as These that the at −1256 as well as the and binding sites in the promoter and were required for expression of the human skeletal actin promoter in the heart. of of not and in expression, that in this do not tissue-specific activation in the heart. In of promoter by about that this element the of the tissue-specific element N.H. L. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar). for specific DNA in the promoter that its activation by p300. Although the promoter in cardiac to that of actin N.H. L. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google of p300 by to in of the and of the binding promoter in cardiac myocytes by and these sites were not required for by p300 of the in the promoter also but not p300 not expression of the promoter at was in the of p300, reflecting interaction of p300 with binding factors S. H.G. E. 1993; Google Scholar). In of the AT-rich motif centered at −1256 not promoter but also by p300 and Although in experiments of the at to p300 this was not and not or of other sites p300 These that transcriptional activation by p300 required a single tissue-specific AT-rich enhancer element in the The is to a MEF-2 binding its homology to sites in other muscle-specific Dev. Biol. 1998; PubMed Scopus Google Scholar). cardiac nuclear proteins binding to the we containing both the and for functional mobility shift were with nuclear extracts from cardiac myocytes and from nuclear proteins with the element at sequence-specific in The required the and not a or the sequence at The complex both and that with the sequence and complexes were as were in cell nuclear extracts and confirmed that MEF-2 proteins bind to the The complexes identified in A were the as well as a MEF-2 The MEF-2 also for the complexes binding to In both and were and by a MEF-2 that MEF-2 and and a control not not MEF-2 is in of tissue-specific complexes to the The homology to a binding from the promoter that is required for its cardiac-specific activation C. L. L. L. T. M. Mol. Cell. Biol. PubMed Scopus Google Scholar). also to the we centered at and −1256 complexes of these but with and with the of complex to the complexes and were by the MEF-2 and complex a to and that of complexes and and not In a selectively complex that was by or of a with complex a binding was as the we observed a single cardiac complex that with complex and was by an oligomer with the a complex that in with complex the and the binding to with a although we the that this binding of In is that the complex the sequence these show that the cardiac-specific element is by at muscle-specific protein containing and with MEF-2 and complexes but sites the motif. for that p300 directly with the MEF-2 DNA-binding The and in A were and to with cardiac nuclear proteins in the or of specific in and the MEF-2 and A with both was by a and These results show that the complex is to or the complex the MEF-2D containing MEF-2D, was also the complex that to p300. A the of p300 with the complex and were not of the complexes the oligomer with the p300 These show that p300 is in a complex with MEF-2D the and not with or other MEF-2 of the are required for formation of this A MEF-2 in the cardiac α-myosin heavy chain promoter is required for in cardiac myocytes J.D. J. Biol. Chem. 1993; Full Text PDF PubMed Google Scholar, J.D. J. Mol. 1996; Full Text PDF PubMed Scopus Google Scholar, J.D. Mol. Cell. Biol. PubMed Google Scholar). were in p300 identified at these or at a binding for the related MADS in the promoter for these are in that the AT-rich from the and complexes to complexes and and In complexes and were by a MEF-2 and complex was by the p300 and No other were of sequence-specific complexes the was by the MEF-2 or p300 These results that p300 with these MADS proteins and is selective for MEF-2 and MEF-2 and p300 to other directly or with we to MEF-2 and p300 from cardiac nuclear both p300 and The MEF-2 was to at MEF-2 we p300 protein in the MEF-2 or p300 the p300 from cardiac nuclear extracts but not MEF-2 not to of the interaction in the of or to the of interaction between the proteins in the of MEF-2 and p300 through DNA we DNA to a containing the MEF-2 as Mol. Cell. Biol. 1998; PubMed Scopus Google Scholar). nuclear proteins binding to this were from the and characterized by with MEF-2 and p300 MEF-2 proteins from the of the a confirmed that the MEF-2D not a to p300 was in the A protein of was also by the and a A not bind to MEF-2 or p300 not These show that cardiac MEF-2 and p300 a specific complex with the and the results of the mobility the functional of the we the proteins cardiac transcription the of the and the promoter containing a in the motif and and in the and of p300 and of the MEF-2 experiments were in cardiac myocytes and of the MEF-2 significantly the or in cardiac although a of activation was in In cardiac activation of the promoter by or not significantly in the of p300 the of MEF-2D and p300 significantly expression, with or p300 is not to the expression of the MEF-2 from these that the of and MEF-2D is to in MEF-2 or the promoter and were at levels in a cell that and expression were not for the not In the of p300 and MEF-2D to transcription of its in cardiac and this activation was of the that cell factors are required for expression of this p300 MEF-2 an the in cardiac These results show that p300 and MEF-2D are for cardiac transcription of the promoter and that this is through the at The skeletal actin gene not been to a for activation by as to the the MEF-2 binding also the or in activation of by p300 through the these a expression was with the and The was at of promoter as of not expression of the promoter at and not and significantly its activation by p300 in the of an intact with the observed of physical interaction in these that is not directly in p300-mediated activation of skeletal actin the transcription factor MEF-2D as a specific physical and functional of p300 in the heart. of the native human skeletal actin promoter by p300 required a single DNA sequence in the a hybrid binding for MEF-2 and Full expression of the skeletal actin promoter required this both in and in p300 exclusively to this as part of a complex with MEF-2D, and not identified in DNA complexes with or in a related p300 and MEF-2D transcriptional activation of the functional was not observed in a requirement for cell these MEF-2D as a for p300 in the and p300 in the regulatory of the cardiac phenotype (10Yao T.P. Oh S.P. Fuchs M. Zhou N.D. Ch'ng L.E. Newsome D. Bronson R.T. Li E. Livingston D.M. Eckner R. Cell. 1998; 93: 361-372Abstract Full Text Full Text PDF PubMed Scopus (810) Google Scholar, N.H. Zeng G.-Q. Sato B. Webster K.A. J. Biol. Chem. 1997; 272: 20584-20594Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar, 16Kirshenbaum L.A. Schneider M.D. J. Biol. Chem. 1995; 270: 7791-7794Abstract Full Text Full Text PDF PubMed Scopus (138) Google Scholar, 17Hasegawa K. Meyers M.B. Kitsis R.N. J. Biol. Chem. 1997; 272: 20049-20054Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar). show that p300 targeting of MEF-2D its interactions with other proteins that bind to the including and SRF. is other have that p300 bind to both and members of the and transcription through their binding sites S. S. D. A. J. Biol. Chem. 1997; 272: Full Text Full Text PDF PubMed Scopus Google Scholar, T. Eckner R. M. Proc. Natl. Acad. Sci. U. S. A. 1998; PubMed Scopus Google Scholar, T. K. T. S. H. S. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar). In we not physical or functional interaction between p300 and the we p300 at binding sites in the heavy chain K. Kitsis R.N. 1997; PubMed Scopus Google or H. J.D. A.W. S. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: PubMed Scopus Google Scholar) not results do not the that and p300 independently of DNA or in required to the between and transcriptional activation in the heart. The MEF-2 of transcription factors to the MADS of DNA-binding characterized by their homology an Although MEF-2 is its in cardiac-specific transcription been well is required for cardiac and not cardiac genes important MEF-2 binding sites Dev. Biol. 1998; PubMed Scopus Google Scholar). MEF-2 DNA-binding and and also bind to proteins as In skeletal MEF-2 proteins with and p300 to and muscle-specific transcription and are thought to in a that J. Y. L. Mol. Cell. Biol. 1997; PubMed Scopus Google Scholar, J.D. Cell. 1995; Full Text PDF PubMed Scopus Google Scholar, R. Yao T.P. E. Livingston D.M. Genes Dev. 1996; PubMed Scopus Google Scholar, Avantaggiati M.L. C. N. A. A. M. J. 1997; PubMed Scopus Google Scholar). for MEF-2 proteins in cardiac transcriptional activation to that the MEF-2D by p300 in to other were to transcriptional activation between p300 and MEF-2D, but not with the other MEF-2 and p300 was to the DNA complex containing do not functional interaction between p300 and other MEF-2 at this but is also that the interaction between the other and p300 is by with is important to are of functional between the MEF-2 MEF-2 are in the heart in Dev. Biol. 1998; PubMed Scopus Google and the AT-rich sequence recruitment of essential coactivator proteins transcriptional activation The observed of between and p300 at this promoter was that p300 and in the and have in and both have in cardiac although these are J. C. 1997; PubMed Scopus Google Scholar). and have closely expression cardiac and expression that of in the cardiac Dev. Biol. 1998; PubMed Scopus Google Scholar). p300 and have been to in J. Y. L. Mol. Cell. Biol. 1997; PubMed Scopus Google Scholar). the physical and functional that interactions to by cell or is that interactions roles in and in important for tissue-specific gene expression in the cardiac of in to its specific The muscle-specific of MEF-2 by expression, or by between MEF-2 binding sites in muscle-specific and genes C. 1999; PubMed Google Scholar). MEF-2 to to control by and by the recruitment of factors J.D. Cell. 1995; Full Text PDF PubMed Scopus Google Scholar, J.D. Mol. Cell. Biol. PubMed Google Scholar, J.D. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: PubMed Scopus Google Scholar). In of this been that transcription is in cell by recruitment of a C. E. J. T. J. 1999; PubMed Scopus Google Scholar). that the is also activation of genes in cardiac muscle recruitment of p300. These to a for MEF-2D in both the activation and signals of enzymes to cardiac-specific promoters. the that MEF-2 and p300 to cardiac-specific Although MEF-2 proteins and p300 have been to in R. Yao T.P. E. Livingston D.M. Genes Dev. 1996; PubMed Scopus Google J. Y. L. Mol. Cell. Biol. 1997; PubMed Scopus Google and at in J. Y. L. Mol. Cell. Biol. 1997; PubMed Scopus Google the of these in tissue-specific transcription been In skeletal the interaction to stabilize complexes R. Yao T.P. E. Livingston D.M. Genes Dev. 1996; PubMed Scopus Google Scholar). that the complex the tissue-specific transcription of that essential and do in the of basic proteins to or Genes Dev. 1995; PubMed Scopus Google Scholar, L. N. H. 1995; PubMed Scopus Google Scholar). that cell factors with MEF-2 and p300 in the cardiac R. D. and E. for the of in this G. Zeng in of of the promoter the of and and the of