TY - JOUR
T1 - CHD7 regulates cardiovascular development through ATP-dependent and -independent activities
AU - Yan, Shun
AU - Thienthanasit, Rassarin
AU - Chen, Dongquan
AU - Engelen, Erik
AU - Brühl, Joanna
AU - Crossman, David K.
AU - Kesterson, Robert
AU - Wang, Qin
AU - Bouazoune, Karim
AU - Jiao, Kai
N1 - Funding Information:
ACKNOWLEDGMENTS. We thank Dr. S. Astrof (Rutgers University) for suggestions on isolation of neural crest cells; Drs. R. Serra, A. Javed, and H. Seo (University of Alabama at Birmingham, UAB) for examination of the craniofacial defects; members in K.J.’s and K.B.’s laboratories for suggestions on this project; the UAB Transgenic & Genetically Engineered Models Core for making the CHD7 (S824F) mouse line using CRISPR/Cas9; the UAB Genomics Core for performing deep-seq and Sanger sequencing; and the UAB Comprehensive Flow Cytometry Facility for sorting neural crest cells. This work was supported by National Institutes of Health Grants 2R01HL095783 and R56 HL130711 (to K.J.); American Heart Association Grant 19TPA34890006 (to K.J.); and Universitätsklinikum Giessen und Marburg Projekt 5/2016 (to K.B.) with additional support from TRR81/3.
Publisher Copyright:
© 2020 National Academy of Sciences. All rights reserved.
PY - 2020/11/17
Y1 - 2020/11/17
N2 - CHD7 encodes an ATP-dependent chromatin remodeling factor. Mutation of this gene causes multiple developmental disorders, including CHARGE (Coloboma of the eye, Heart defects, Atresia of the choanae, Retardation of growth/development, Genital abnormalities, and Ear anomalies) syndrome, in which conotruncal anomalies are the most prevalent form of heart defects. How CHD7 regulates conotruncal development remains unclear. In this study, we establish that deletion of Chd7 in neural crest cells (NCCs) causes severe conotruncal defects and perinatal lethality, thus providing mouse genetic evidence demonstrating that CHD7 cell-autonomously regulates cardiac NCC development, thereby clarifying a long-standing controversy in the literature. Using transcriptomic analyses, we show that CHD7 fine-tunes the expression of a gene network that is critical for cardiac NCC development. To gain further molecular insights into gene regulation by CHD7, we performed a protein–protein interaction screen by incubating recombinant CHD7 on a protein array. We find that CHD7 directly interacts with several developmental disorder-mutated proteins including WDR5, a core component of H3K4 methyltransferase complexes. This direct interaction suggested that CHD7 may recruit histone-modifying enzymes to target loci independently of its remodeling functions. We therefore generated a mouse model that harbors an ATPase-deficient allele and demonstrates that mutant CHD7 retains the ability to recruit H3K4 methyltransferase activity to its targets. Thus, our data uncover that CHD7 regulates cardiovascular development through ATP-dependent and -independent activities, shedding light on the etiology of CHD7-related congenital disorders. Importantly, our data also imply that patients carrying a premature stop codon versus missense mutations will likely display different molecular alterations; these patients might therefore require personalized therapeutic interventions.
AB - CHD7 encodes an ATP-dependent chromatin remodeling factor. Mutation of this gene causes multiple developmental disorders, including CHARGE (Coloboma of the eye, Heart defects, Atresia of the choanae, Retardation of growth/development, Genital abnormalities, and Ear anomalies) syndrome, in which conotruncal anomalies are the most prevalent form of heart defects. How CHD7 regulates conotruncal development remains unclear. In this study, we establish that deletion of Chd7 in neural crest cells (NCCs) causes severe conotruncal defects and perinatal lethality, thus providing mouse genetic evidence demonstrating that CHD7 cell-autonomously regulates cardiac NCC development, thereby clarifying a long-standing controversy in the literature. Using transcriptomic analyses, we show that CHD7 fine-tunes the expression of a gene network that is critical for cardiac NCC development. To gain further molecular insights into gene regulation by CHD7, we performed a protein–protein interaction screen by incubating recombinant CHD7 on a protein array. We find that CHD7 directly interacts with several developmental disorder-mutated proteins including WDR5, a core component of H3K4 methyltransferase complexes. This direct interaction suggested that CHD7 may recruit histone-modifying enzymes to target loci independently of its remodeling functions. We therefore generated a mouse model that harbors an ATPase-deficient allele and demonstrates that mutant CHD7 retains the ability to recruit H3K4 methyltransferase activity to its targets. Thus, our data uncover that CHD7 regulates cardiovascular development through ATP-dependent and -independent activities, shedding light on the etiology of CHD7-related congenital disorders. Importantly, our data also imply that patients carrying a premature stop codon versus missense mutations will likely display different molecular alterations; these patients might therefore require personalized therapeutic interventions.
KW - CHARGE syndrome | cardiac neural crest cells | cardiovascular development | nucleosome remodeling | CHD7
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U2 - 10.1073/pnas.2005222117
DO - 10.1073/pnas.2005222117
M3 - Article
C2 - 33127760
AN - SCOPUS:85096355877
SN - 0027-8424
VL - 117
SP - 28847
EP - 28858
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 46
ER -