CHD4 and the NuRD complex directly control cardiac sarcomere formation

Proc Natl Acad Sci U S A. 2018 Jun 26;115(26):6727-6732. doi: 10.1073/pnas.1722219115. Epub 2018 Jun 11.


Cardiac development relies on proper cardiomyocyte differentiation, including expression and assembly of cell-type-specific actomyosin subunits into a functional cardiac sarcomere. Control of this process involves not only promoting expression of cardiac sarcomere subunits but also repressing expression of noncardiac myofibril paralogs. This level of transcriptional control requires broadly expressed multiprotein machines that modify and remodel the chromatin landscape to restrict transcription machinery access. Prominent among these is the nucleosome remodeling and deacetylase (NuRD) complex, which includes the catalytic core subunit CHD4. Here, we demonstrate that direct CHD4-mediated repression of skeletal and smooth muscle myofibril isoforms is required for normal cardiac sarcomere formation, function, and embryonic survival early in gestation. Through transcriptomic and genome-wide analyses of CHD4 localization, we identified unique CHD4 binding sites in smooth muscle myosin heavy chain, fast skeletal α-actin, and the fast skeletal troponin complex genes. We further demonstrate that in the absence of CHD4, cardiomyocytes in the developing heart form a hybrid muscle cell that contains cardiac, skeletal, and smooth muscle myofibril components. These misexpressed paralogs intercalate into the nascent cardiac sarcomere to disrupt sarcomere formation and cause impaired cardiac function in utero. These results demonstrate the genomic and physiological requirements for CHD4 in mammalian cardiac development.

Keywords: chromatin; congenital heart disease; heart; nucleosome remodeling and deacetylase complex; sarcomere.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural

MeSH terms

  • Animals
  • DNA Helicases / chemistry
  • DNA Helicases / deficiency
  • DNA Helicases / physiology*
  • Female
  • Gene Expression Regulation, Developmental*
  • Gene Knockdown Techniques
  • Genes, Lethal
  • Heart / diagnostic imaging
  • Heart / embryology
  • Heart Defects, Congenital / diagnostic imaging
  • Heart Defects, Congenital / embryology
  • Heart Defects, Congenital / genetics*
  • Heart Defects, Congenital / pathology
  • Male
  • Mi-2 Nucleosome Remodeling and Deacetylase Complex / physiology*
  • Mice
  • Muscle Proteins / biosynthesis
  • Muscle Proteins / genetics
  • Myocytes, Cardiac / physiology*
  • Myofibrils / metabolism
  • Myofibrils / pathology
  • Nucleosomes / metabolism
  • Nucleosomes / ultrastructure
  • Sarcomeres / physiology*
  • Sarcomeres / ultrastructure
  • Transcription, Genetic
  • Ultrasonography, Prenatal


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