Combined impairments in hearing, vision, olfaction, and pain perception are a major contributor to neurocognitive disabilities and adaptive functioning worldwide. Nearly one-third of the population suffers from sensory disorders involving taste, smell, hearing, or balance in their lifetime. Current treatments for congenital or acquired sensory impairments are strictly supportive, and there is a critical unmet need for the development of regenerative therapies. CHARGE Syndrome is a multiple sensory disorder second only to Usher Syndrome as a cause of deaf blindness. CHARGE is characterized by ocular coloboma, heart defects, atresia of the choanae, retardation of growth and development (including intellectual disability and autism), genital hypoplasia (including hypogonadotropic hypogonadism), and ear defects including deafness and inner ear dysplasia. CHARGE is caused by heterozygous mutations in the CHD7 gene encoding a DNA binding ATP- dependent chromatin remodeling protein. Study of CHD7 function is relevant for multiple sensory disorders, as it is highly expressed during development and in mature ear, eye, nasal, craniofacial, brain, and craniofacial tissues. CHD7 binds to methylated histones at enhancer sequences and transcription start sites throughout the genome, in a tissue and developmental stage-specific manner. Current challenges include identification of important target genes and signaling pathways that mediate the cellular effects of CHD7, and determination of whether mammalian CHD7 deficiency phenotypes can be prevented or reversed. Our laboratory has studied mouse models of CHARGE Syndrome and found that CHD7 is a major positive regulator of neural stem cell proliferation in the olfactory epithelium, inner ear, and forebrain subventricular zone. Interestingly, there is significant overlap in phenotypes between CHARGE Syndrome, retinoic acid embryopathy, and vitamin A deficiency in both humans and mice, raising the possibility that control of vitamin A levels may influence CHD7 effects. Preliminary data indicate that altered retinoic acid signaling partially rescues Chd7 heterozygous null phenotypes, suggesting CHD7 and retinoic acid function through common signaling pathways. We have developed the global hypothesis that CHD7 and retinoic acid signaling share common mechanisms or genetic targets that are necessary for proper development of craniofacial structures and neural stem cell proliferation. We propose four aims to test this hypothesis: (1) Determine whether up-regulation of retinoic acid signaling is an essential component of the phenotypes observed in Chd7 deficient mice, (2) Evaluate CHD7- dependence of retinoic acid signaling in proliferation of mouse neural progenitors, (3) Identify common retinoic acid signaling and CHD7 binding sites in neural stem cells, and (4) Test recently generated human induced pluripotent stem cells from CHD7-mutation positive CHARGE individuals for retinoic acid dependent proliferation and differentiation. Results will identify basic mechanisms of chromatin-mediated gene expression in mammalian cells and help establish a basis for the rationale design of pre-clinical trials.

Public Health Relevance

This project has direct relevance for diagnosis and treatment of disorders that negatively impact hearing, vision, balance, and cognition, as well as development of the heart, skeleton, and craniofacial structures. Results of experiments described in this proposal will enhance our understanding of genetic and epigenetic factors regulating chromatin biology in neuronal and craniofacial tissues, and provide critical information for improved stem cell and regenerative medicine.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Research Project (R01)
Project #
2R01DC009410-06
Application #
8580397
Study Section
Genetics of Health and Disease Study Section (GHD)
Program Officer
Freeman, Nancy
Project Start
2008-04-01
Project End
2018-11-30
Budget Start
2013-12-01
Budget End
2014-11-30
Support Year
6
Fiscal Year
2014
Total Cost
$450,486
Indirect Cost
$117,213
Name
University of Michigan Ann Arbor
Department
Pediatrics
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Choo, Daniel I; Tawfik, Kareem O; Martin, Donna M et al. (2017) Inner ear manifestations in CHARGE: Abnormalities, treatments, animal models, and progress toward treatments in auditory and vestibular structures. Am J Med Genet C Semin Med Genet 175:439-449
Bird, Jonathan E; Barzik, Melanie; Drummond, Meghan C et al. (2017) Harnessing molecular motors for nanoscale pulldown in live cells. Mol Biol Cell 28:463-475
Moccia, Amanda; Martin, Donna M (2017) Nervous system development and disease: A focus on trithorax related proteins and chromatin remodelers. Mol Cell Neurosci :
Charoy, Camille; Dinvaut, Sarah; Chaix, Yohan et al. (2017) Genetic specification of left-right asymmetry in the diaphragm muscles and their motor innervation. Elife 6:
Kong, Fang; Martin, Donna M (2017) Atopic disorders in CHARGE syndrome: A retrospective study and literature review. Eur J Med Genet :
Blake, Kim; Trider, Carrie-Lee; Hartshorne, Timothy S et al. (2016) Correspondence to Hale et al. atypical phenotypes associated with pathogenic CHD7 variants and a proposal for broadening CHARGE syndrome clinical diagnostic criteria. Am J Med Genet A 170:3365-3366
Harel, Tamar; Yoon, Wan Hee; Garone, Caterina et al. (2016) Recurrent De Novo and Biallelic Variation of ATAD3A, Encoding a Mitochondrial Membrane Protein, Results in Distinct Neurological Syndromes. Am J Hum Genet 99:831-845
Hale, Caitlin L; Niederriter, Adrienne N; Green, Glenn E et al. (2016) Atypical phenotypes associated with pathogenic CHD7 variants and a proposal for broadening CHARGE syndrome clinical diagnostic criteria. Am J Med Genet A 170A:344-54
Lee, Min Young; Kurioka, Takaomi; Nelson, Megan M et al. (2016) Viral-mediated Ntf3 overexpression disrupts innervation and hearing in nondeafened guinea pig cochleae. Mol Ther Methods Clin Dev 3:16052
Martin, Donna M; Salem-Hartshorne, Nancy; Hartshorne, Timothy S et al. (2016) 12th International CHARGE syndrome conference proceedings. Am J Med Genet A 170A:856-69

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