The Chromatin Remodeling Complex Chd4/NuRD Controls Striated Muscle Identity and Metabolic Homeostasis

Cell Metab. 2016 May 10;23(5):881-92. doi: 10.1016/j.cmet.2016.04.008.


Heart muscle maintains blood circulation, while skeletal muscle powers skeletal movement. Despite having similar myofibrilar sarcomeric structures, these striated muscles differentially express specific sarcomere components to meet their distinct contractile requirements. The mechanism responsible is still unclear. We show here that preservation of the identity of the two striated muscle types depends on epigenetic repression of the alternate lineage gene program by the chromatin remodeling complex Chd4/NuRD. Loss of Chd4 in the heart triggers aberrant expression of the skeletal muscle program, causing severe cardiomyopathy and sudden death. Conversely, genetic depletion of Chd4 in skeletal muscle causes inappropriate expression of cardiac genes and myopathy. In both striated tissues, mitochondrial function was also dependent on the Chd4/NuRD complex. We conclude that an epigenetic mechanism controls cardiac and skeletal muscle structural and metabolic identities and that loss of this regulation leads to hybrid striated muscle tissues incompatible with life.

MeSH terms

  • Aging / pathology
  • Animals
  • Cardiomyopathies / metabolism
  • Cardiomyopathies / pathology
  • Cell Differentiation / genetics
  • Chromatin Assembly and Disassembly*
  • CpG Islands / genetics
  • DNA Helicases / metabolism*
  • Gene Expression Regulation, Developmental
  • Heart / embryology
  • Homeostasis*
  • Mi-2 Nucleosome Remodeling and Deacetylase Complex / metabolism*
  • Mice, Transgenic
  • Mitochondria, Heart / metabolism
  • Muscle, Striated / embryology
  • Muscle, Striated / metabolism*
  • Myocytes, Cardiac / metabolism
  • Myocytes, Cardiac / pathology
  • Promoter Regions, Genetic / genetics
  • Protein Binding


  • Mi-2 Nucleosome Remodeling and Deacetylase Complex
  • Mi-2beta protein, mouse
  • DNA Helicases