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

Yuelong Liu, Cristina Harmelink, Yin Peng, Yunjia Chen, Qin Wang, Kai Jiao

Research output: Contribution to journalArticlepeer-review

39 Scopus citations

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, itremains unclear whether CHD7 can directly regulate cardiogenic genesin 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 amajor contribution to CHDs in CHARGE syndrome.

Original languageEnglish (US)
Article numberddt610
Pages (from-to)2145-2156
Number of pages12
JournalHuman Molecular Genetics
Volume23
Issue number8
DOIs
StatePublished - Apr 2014
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

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