CHD7 interacts with BMP R-SMADs to epigenetically regulate cardiogenesis in mice

Hum Mol Genet. 2014 Apr 15;23(8):2145-56. doi: 10.1093/hmg/ddt610. Epub 2013 Nov 29.

Abstract

Haploinsufficiency for CHD7, an ATP-dependent nucleosome remodeling factor, is the leading cause of CHARGE syndrome. While congenital heart defects (CHDs) are major clinical features of CHARGE syndrome, affecting >75% of patients, it remains unclear whether CHD7 can directly regulate cardiogenic genes in embryos. Our complementary yeast two-hybrid and biochemical assays reveal that CHD7 is a novel interaction partner of canonical BMP signaling pathway nuclear mediators, SMAD1/5/8, in the embryonic heart. Moreover, CHD7 associates in a BMP-dependent manner with the enhancers of a critical cardiac transcription factor, Nkx2.5, that contain functional SMAD1-binding elements. Both the active epigenetic signature of Nkx2.5 regulatory elements and its proper expression in cardiomyocytes require CHD7. Finally, inactivation of Chd7 in mice impairs multiple BMP signaling-regulated cardiogenic processes. Our results thus support the model that CHD7 is recruited by SMAD1/5/8 to the enhancers of BMP-targeted cardiogenic genes to epigenetically regulate their expression. Impaired BMP activities in embryonic hearts may thus have a major contribution to CHDs in CHARGE syndrome.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blotting, Western
  • Bone Morphogenetic Protein 1 / genetics
  • Bone Morphogenetic Protein 1 / metabolism*
  • Cells, Cultured
  • Chromatin Immunoprecipitation
  • DNA-Binding Proteins / physiology*
  • Embryo, Mammalian / cytology
  • Embryo, Mammalian / metabolism*
  • Epigenomics*
  • Gene Expression Regulation, Developmental
  • Heart / embryology*
  • Homeobox Protein Nkx-2.5
  • Homeodomain Proteins / genetics*
  • Homeodomain Proteins / metabolism
  • Immunoenzyme Techniques
  • Immunoprecipitation
  • Mice
  • Organogenesis / physiology
  • Protein Binding
  • RNA, Messenger / genetics
  • Real-Time Polymerase Chain Reaction
  • Regulatory Elements, Transcriptional
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction
  • Smad Proteins, Receptor-Regulated / genetics
  • Smad Proteins, Receptor-Regulated / metabolism*
  • Transcription Factors / genetics*
  • Transcription Factors / metabolism
  • Transcription, Genetic
  • Two-Hybrid System Techniques

Substances

  • Chd7 protein, mouse
  • DNA-Binding Proteins
  • Homeobox Protein Nkx-2.5
  • Homeodomain Proteins
  • Nkx2-5 protein, mouse
  • RNA, Messenger
  • Smad Proteins, Receptor-Regulated
  • Transcription Factors
  • Bmp1 protein, mouse
  • Bone Morphogenetic Protein 1