title: Myocardin is a bifunctional switch for smooth versus skeletal muscle differentiation.
abstract: Skeletal and smooth muscle can mutually transdifferentiate, but little molecular insight exists as to how each muscle program may be subverted to the other. The myogenic basic helix-loop-helix transcription factors MyoD and myogenin (Myog) direct the development of skeletal muscle and are thought to be dominant over the program of smooth muscle cell (SMC) differentiation. Myocardin (Myocd) is a serum response factor (SRF) coactivator that promotes SMC differentiation through transcriptional stimulation of SRF-dependent smooth muscle genes. Here we show by lineage-tracing studies that Myocd is expressed transiently in skeletal muscle progenitor cells of the somite, and a majority of skeletal muscle is derived from Myocd-expressing cell lineages. However, rather than activating skeletal muscle-specific gene expression, Myocd functions as a transcriptional repressor of Myog, inhibiting skeletal muscle differentiation while activating SMC-specific genes. This repressor function of Myocd is complex, involving histone deacetylase 5 silencing of the Myog promoter and Myocd's physical contact with MyoD, which undermines MyoD DNA binding and transcriptional synergy with MEF2. These results reveal a previously unrecognized role for Myocd in repressing the skeletal muscle differentiation program and suggest that this transcriptional coregulator acts as a bifunctional molecular switch for the smooth versus skeletal muscle phenotypes.
authors.affiliation: The Aab Cardiovascular Research Institute, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA.
authors.forename: Xiaochun
authors.initials: X
authors.lastname: Long
authors.forename: Esther E
authors.initials: EE
authors.lastname: Creemers
authors.forename: Da-Zhi
authors.initials: DZ
authors.lastname: Wang
authors.forename: Eric N
authors.initials: EN
authors.lastname: Olson
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Miano
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D004247:DNA / Q000378:metabolism; D015536:Down-Regulation; D018507:Gene Expression Regulation, Developmental; D006655:Histone Deacetylases / Q000378:metabolism; D064326:MEF2 Transcription Factors; D051379:Mice; D024510:Muscle Development / Q000235:genetics*; D018482:Muscle, Skeletal / Q000166:cytology / Q000196:embryology* / Q000378:metabolism; D009130:Muscle, Smooth / Q000166:cytology / Q000196:embryology* / Q000378:metabolism; D017570:MyoD Protein / Q000378:metabolism; D032446:Myoblasts / Q000166:cytology / Q000378:metabolism; D018006:Myogenic Regulatory Factors / Q000378:metabolism; D018008:Myogenin / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics / Q000502:physiology*; D011401:Promoter Regions, Genetic; D015534:Trans-Activators / Q000235:genetics / Q000502:physiology*; D000099251:Myocardin
chemical_list: D004247:DNA; D006655:Histone Deacetylases; D064326:MEF2 Transcription Factors; D017570:MyoD Protein; D018006:Myogenic Regulatory Factors; D018008:Myogenin; D009687:Nuclear Proteins; D015534:Trans-Activators; D000099251:Myocardin; C578036:Mef2a protein, mouse; C057363:MyoD1 myogenic differentiation protein; C498618:Hdac5 protein, mouse