Heterozygous mutations in the gene encoding CHD7, an ATP-dependent chromatin remodeler homologous to the Drosophila trithorax group protein Kismet, result in a complex constellation of congenital anomalies called CHARGE syndrome, a sporadic, autosomal dominant disorder characterized by malformations of the craniofacial structures, peripheral nervous system, ears, eyes and heart. Preliminary work implicated defective formation of the neural crest in CHARGE syndrome etiology. Neural crest is a transient cell population that is ectodermal in origin, but undergoes a major transcriptional reprogramming to acquire a remarkably broad differentiation potential and ability to migrate throughout the body to give rise to craniofacial bones and cartilages, peripheral nervous system, and cardiac structures. However, the role of chromatin remodeling in this process is not well understood. This application addresses mechanisms underlying CHD7 dysfunction in CHARGE syndrome. CHARGE-patient specific induced pluripotent stem cell lines will be developed, and used as a tool for disease modeling and characterization of cellular and molecular deficits associated with CHARGE genotypes. In parallel, frog embryo model will be used to study effects of CHARGE-associated CHD7 mutations in vivo. This studies will be complemented by biochemical analyses of CHD7 mutants in human cells. Finally, genomic approaches will be utilized for genome-wide identification of regulatory elements active in human neural crest cells. This analysis will pinpoint genomic sequences whose variation can confer susceptibility to some of the most common birth defects, such as craniofacial dysmorphisms including cleft lip and/or palate, heart malformations and peripheral nervous system defects.

Public Health Relevance

Research proposed here will uncover molecular and cellular mechanisms underlying CHARGE syndrome, a leading cause of deaf-blindness, congenital heart disease and craniofacial malformations. Our work will advance understanding and diagnosis of this multisystemic syndrome and may lead to improved clinical interventions in patients. In addition, we will identify a set of candidate genomic sequences whose mutations may confer susceptibility to some of the most common birth defects, such as craniofacial dysmorphisms including cleft lip and/or palate, heart malformations and peripheral nervous system defects.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Molecular Genetics B Study Section (MGB)
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Krasnewich, Donna M
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Stanford University
Schools of Medicine
United States
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Nady, Nataliya; Gupta, Ankit; Ma, Ziyang et al. (2015) ETO family protein Mtgr1 mediates Prdm14 functions in stem cell maintenance and primordial germ cell formation. Elife 4:e10150
Prescott, Sara L; Srinivasan, Rajini; Marchetto, Maria Carolina et al. (2015) Enhancer divergence and cis-regulatory evolution in the human and chimp neural crest. Cell 163:68-83
Calo, Eliezer; Flynn, Ryan A; Martin, Lance et al. (2015) RNA helicase DDX21 coordinates transcription and ribosomal RNA processing. Nature 518:249-53
Van Nostrand, Jeanine L; Brady, Colleen A; Jung, Heiyoun et al. (2014) Inappropriate p53 activation during development induces features of CHARGE syndrome. Nature 514:228-32
Calo, Eliezer; Wysocka, Joanna (2013) Modification of enhancer chromatin: what, how, and why? Mol Cell 49:825-37
Rada-Iglesias, Alvaro; Prescott, Sara L; Wysocka, Joanna (2013) Human genetic variation within neural crest enhancers: molecular and phenotypic implications. Philos Trans R Soc Lond B Biol Sci 368:20120360
Rada-Iglesias, Alvaro; Bajpai, Ruchi; Prescott, Sara et al. (2012) Epigenomic annotation of enhancers predicts transcriptional regulators of human neural crest. Cell Stem Cell 11:633-48
Buecker, Christa; Wysocka, Joanna (2012) Enhancers as information integration hubs in development: lessons from genomics. Trends Genet 28:276-84