title: 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.affiliation: Department of Genetics and Department of Cell, Developmental and Integrative Biology, The University of Alabama at Birmingham, Birmingham, AL 35294, USA
authors.forename: Yuelong
authors.initials: Y
authors.lastname: Liu
authors.forename: Cristina
authors.initials: C
authors.lastname: Harmelink
authors.forename: Yin
authors.initials: Y
authors.lastname: Peng
authors.forename: Yunjia
authors.initials: Y
authors.lastname: Chen
authors.forename: Qin
authors.initials: Q
authors.lastname: Wang
authors.forename: Kai
authors.initials: K
authors.lastname: Jiao
mesh_terms: D000818:Animals; D015153:Blotting, Western; D055395:Bone Morphogenetic Protein 1 / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D004268:DNA-Binding Proteins / Q000502:physiology*; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism*; D057890:Epigenomics; D018507:Gene Expression Regulation, Developmental; D006321:Heart / Q000196:embryology*; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D007124:Immunoenzyme Techniques; D047468:Immunoprecipitation; D051379:Mice; D038081:Organogenesis / Q000502:physiology; D011485:Protein Binding; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D050436:Regulatory Elements, Transcriptional; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D051896:Smad Proteins, Receptor-Regulated / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic; D020798:Two-Hybrid System Techniques
chemical_list: C507367:Chd7 protein, mouse; D004268:DNA-Binding Proteins; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins; C484469:Nkx2-5 protein, mouse; D012333:RNA, Messenger; D051896:Smad Proteins, Receptor-Regulated; D014157:Transcription Factors; C525707:Bmp1 protein, mouse; D055395:Bone Morphogenetic Protein 1