title: PC4 coactivates MyoD by relieving the histone deacetylase 4-mediated inhibition of myocyte enhancer factor 2C.
abstract: 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.
authors.affiliation: Istituto di Neurobiologia e Medicina Molecolare, Consiglio Nazionale delle Ricerche, Viale Marx 15, 00137, Rome, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Micheli
authors.forename: Luca
authors.initials: L
authors.lastname: Leonardi
authors.forename: Filippo
authors.initials: F
authors.lastname: Conti
authors.forename: Pasquale
authors.initials: P
authors.lastname: Buanne
authors.forename: Nadia
authors.initials: N
authors.lastname: Canu
authors.forename: Maurizia
authors.initials: M
authors.lastname: Caruso
authors.forename: Felice
authors.initials: F
authors.lastname: Tirone
mesh_terms: 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
chemical_list: 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
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