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.
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Authors | Yuelong Liu, Cristina Harmelink, Yin Peng, Yunjia Chen, Qin Wang, Kai Jiao |
Journal | Human molecular genetics
(Hum Mol Genet)
Vol. 23
Issue 8
Pg. 2145-56
(Apr 15 2014)
ISSN: 1460-2083 [Electronic] England |
PMID | 24293546
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Chemical References |
- 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
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Topics |
- Animals
- Blotting, Western
- Bone Morphogenetic Protein 1
(genetics, metabolism)
- Cells, Cultured
- Chromatin Immunoprecipitation
- DNA-Binding Proteins
(physiology)
- Embryo, Mammalian
(cytology, metabolism)
- Epigenomics
- Gene Expression Regulation, Developmental
- Heart
(embryology)
- Homeobox Protein Nkx-2.5
- Homeodomain Proteins
(genetics, 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, metabolism)
- Transcription Factors
(genetics, metabolism)
- Transcription, Genetic
- Two-Hybrid System Techniques
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