Myocardin is a bifunctional switch for smooth versus skeletal muscle differentiation

Xiaochun Long, Esther E. Creemers, Da Zhi Wang, Eric N. Olson, Joseph M. Miano

Research output: Contribution to journalArticle

58 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)16570-16575
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume104
Issue number42
DOIs
StatePublished - Oct 16 2007

Fingerprint

Skeletal Muscle
Myogenin
Serum Response Factor
Smooth Muscle Myocytes
Smooth Muscle
Cell Differentiation
Basic Helix-Loop-Helix Transcription Factors
Somites
Histone Deacetylases
myocardin
Cell Lineage
Muscle Cells
Genes
Stem Cells
Phenotype
Gene Expression
Muscles
DNA

Keywords

  • Deacetylase
  • MEF2
  • Myogenic
  • Promoter
  • SRF

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Myocardin is a bifunctional switch for smooth versus skeletal muscle differentiation. / Long, Xiaochun; Creemers, Esther E.; Wang, Da Zhi; Olson, Eric N.; Miano, Joseph M.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 104, No. 42, 16.10.2007, p. 16570-16575.

Research output: Contribution to journalArticle

Long, Xiaochun ; Creemers, Esther E. ; Wang, Da Zhi ; Olson, Eric N. ; Miano, Joseph M. / Myocardin is a bifunctional switch for smooth versus skeletal muscle differentiation. In: Proceedings of the National Academy of Sciences of the United States of America. 2007 ; Vol. 104, No. 42. pp. 16570-16575.
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