Functions of chromatin remodeler Chd7 in retinal cell development

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CHD7 (Chromodomain helicase DNA-binding 7) is an ATP-dependent chromatin remodeling protein that has critical functions in neurogenesis and neural crest cell development. Pathogenic variants in CHD7 are the most common cause of CHARGE syndrome or CHD7 disorder, a complex genetic syndrome characterized by ocular coloboma, heart abnormalities, choanal atresia, retardation of growth, genitourinary defects, and hearing loss, as well as other developmental defects. Although some studies have examined the molecular basis for the early ocular defects (such as coloboma) resulting from CHD7 pathogenic variants, it is not known whether there is a continuing requirement for CHD7 in the developing retina once ocular morphogenesis is complete. We have recently shown that CHD7 is robustly expressed in subsets of newly differentiated retinal cell types, including rod and cone photoreceptors, as well as in proliferating retinal progenitor cells. Furthermore, zebrafish and mouse Chd7 mutants display reductions in cone photoreceptor number and abnormally small photoreceptor outer segments, suggesting a critical role for CHD7 in photoreceptor differentiation and outer segment morphogenesis. We hypothesize that the chromatin remodeling function of CHD7 is necessary for the transcriptional activation of genes promoting retinal cell type differentiation and genes involved in photoreceptor outer segment morphogenesis. In this proposal, we will test this hypothesis through a combination of zebrafish and mouse genetics, transcriptomic and epigenomic analyses, and studies of human retinal organoids and human retinal imaging. Results from these studies will contribute to our understanding of the genetic and epigenetic regulation of retinal cell type development as well as the pathogenesis of visual system defects associated with CHD7 disorder.