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
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Blotting, Western
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Bone Morphogenetic Protein 1 / genetics
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Bone Morphogenetic Protein 1 / metabolism*
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Cells, Cultured
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Chromatin Immunoprecipitation
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DNA-Binding Proteins / physiology*
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Embryo, Mammalian / cytology
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Embryo, Mammalian / metabolism*
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Epigenomics*
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Gene Expression Regulation, Developmental
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Heart / embryology*
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Homeobox Protein Nkx-2.5
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Homeodomain Proteins / genetics*
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Homeodomain Proteins / metabolism
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Immunoenzyme Techniques
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Immunoprecipitation
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Mice
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Organogenesis / physiology
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Protein Binding
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RNA, Messenger / genetics
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Real-Time Polymerase Chain Reaction
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Regulatory Elements, Transcriptional
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Reverse Transcriptase Polymerase Chain Reaction
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Signal Transduction
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Smad Proteins, Receptor-Regulated / genetics
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Smad Proteins, Receptor-Regulated / metabolism*
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Transcription Factors / genetics*
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Transcription Factors / metabolism
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Transcription, Genetic
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Two-Hybrid System Techniques
Substances
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Chd7 protein, mouse
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DNA-Binding Proteins
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Homeobox Protein Nkx-2.5
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Homeodomain Proteins
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Nkx2-5 protein, mouse
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RNA, Messenger
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Smad Proteins, Receptor-Regulated
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Transcription Factors
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Bmp1 protein, mouse
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Bone Morphogenetic Protein 1