These studies have direct relevance for improving our understanding of the developmental defects associated with Chd7 deficiency. Precise regulation of gene expression is critical for normal development of most tissues and organs. Chromodomain proteins, characterized by DNA binding and ATP-dependent helicase domains, have poorly understood roles in chromatin remodeling and exert epigenetic influences on gene expression. In humans, haploinsufficiency for CHD7, a member of the third subfamily of chromodomain proteins, causes CHARGE syndrome. CHARGE is a multiple anomaly disorder characterized by ocular coloboma, heart defects, atresia of the choanae, retarded growth and development, genital hypoplasia, and ear anomalies including deafness and vestibular disorders. We generated mice heterozygous for a gene trapped null allele (Chd7Gt/+). These mice exhibit many features similar to human CHARGE phenotypes, including severe inner ear defects and postnatal growth delays. Chd7Gt/+ mice also express a ?-galactosidase reporter in Chd7-positive tissues, and can be used for tracking the fates of Chd7 deficient cells. The clinical features of CHARGE in humans and mice are variable and incompletely penetrant, and the most common developmental malformation in both humans and mice with loss of CHD7 function is semicircular canal dysgenesis or hypoplasia. Inner ear defects with Chd7 deficiency in mice are complex, and include malformations of the semicircular canals and innervation of sensory epithelia. Specific tissues and cell types appear uniquely sensitive to Chd7 dosage, but the cellular Chd7 expression patterns and mechanisms of Chd7 deficiency in cell proliferation, differentiation, and survival are not known. Moreover, CHD7 interacting partners and downstream targets in the ear and neural cells are not characterized. Such knowledge would help guide rational development of therapies for inner ear defects. Our global hypothesis is that CHD7 functions in a transcriptional complex to repress or activate downstream target genes in developing ear and neural tissues. We have three specific aims: (1) Characterize cell proliferation, survival, and differentiation in Chd7 mutant mice, (2) Determine the contributions of CHD7-expressing tissues to inner ear development, and (3) Characterize cultured inner ear and neural stem cells from wildtype and Chd7 mutant embryos, and use them to determine whether CHD7 directly binds the promoters of candidate target genes. Results of proposed experiments will bring novel insights into fundamental processes of chromatin remodeling and transcriptional regulation. Improved understanding of tissue-specific requirements for Chd7 might also improve the diagnosis and treatment of CHARGE-related inner ear and other developmental defects.

Public Health Relevance

This project has direct relevance for understanding the mechanisms of CHD7 deficiency-induced hearing and balance disorders in children and adults with CHARGE syndrome. CHARGE syndrome is a multiple anomaly condition that affects 1 in 10,000 newborn children worldwide. Results of experiments described in this proposal will improve our understanding of genetic and epigenetic factors regulating basic chromatin biology, and their impact on development.

National Institute of Health (NIH)
National Institute on Deafness and Other Communication Disorders (NIDCD)
Research Project (R01)
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Genetics of Health and Disease Study Section (GHD)
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Freeman, Nancy
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University of Michigan Ann Arbor
Schools of Medicine
Ann Arbor
United States
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Kong, Fang; Martin, Donna M (2018) Atopic disorders in CHARGE syndrome: A retrospective study and literature review. Eur J Med Genet 61:225-229
Ritter, K Elaine; Martin, Donna M (2018) Neural crest contributions to the ear: Implications for congenital hearing disorders. Hear Res :
Martin, Donna M; Rathmell, W Kimryn; Tavazoie, Sohail F (2018) Balancing dual demands on the physician-scientist workforce. J Clin Invest 128:3204-3205
Moccia, Amanda; Srivastava, Anshika; Skidmore, Jennifer M et al. (2018) Genetic analysis of CHARGE syndrome identifies overlapping molecular biology. Genet Med 20:1022-1029
Devare, Jenna; Gubbels, Samuel; Raphael, Yehoash (2018) Outlook and future of inner ear therapy. Hear Res 368:127-135
Durruthy-Durruthy, Robert; Sperry, Ethan D; Bowen, Margot E et al. (2018) Single Cell Transcriptomics Reveal Abnormalities in Neurosensory Patterning of the Chd7 Mutant Mouse Ear. Front Genet 9:473
Moccia, Amanda; Martin, Donna M (2018) Nervous system development and disease: A focus on trithorax related proteins and chromatin remodelers. Mol Cell Neurosci 87:46-54
Bélanger, Catherine; Bérubé-Simard, Félix-Antoine; Leduc, Elizabeth et al. (2018) Dysregulation of cotranscriptional alternative splicing underlies CHARGE syndrome. Proc Natl Acad Sci U S A 115:E620-E629
Iwase, Shigeki; Martin, Donna M (2018) Chromatin in nervous system development and disease. Mol Cell Neurosci 87:1-3
Marie, Corentine; Clavairoly, Adrien; Frah, Magali et al. (2018) Oligodendrocyte precursor survival and differentiation requires chromatin remodeling by Chd7 and Chd8. Proc Natl Acad Sci U S A 115:E8246-E8255

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