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

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.

• 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)

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

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