ABSTRACT
Epigenetic regulation of gene expression occurs via heritable changes in DNA and associated histone proteins.
Such modifications, which include methylation, acetylation, and nucleosome repositioning, have a major and
poorly understood role in development and disease. Recent studies have begun to explore epigenetics of
hearing and balance disorders which negatively impact quality of life and impose a significant socioeconomic
burden on millions of Americans. In both children and adults with hearing or balance disorders, development of
the cochlear epithelium, vestibular epithelia and associated neurons are often disrupted. During inner ear
development, neurosensory progenitors from the otic vesicle give rise to sensory hair cells and
vestibulocochlear neurons. Mutations and epigenetic changes in genes that perturb otic development often
cause improper hair cell and neuron formation, resulting in hearing loss. The chromodomain helicase DNA
binding protein 7 (CHD7) is an ATP dependent epigenetic chromatin remodeler implicated in inner ear
development. Mutations in CHD7 cause CHARGE syndrome (ocular Coloboma, Heart defects, Atresia of the
choanae, Retardation of growth and development, Genital hypoplasia and pubertal delay, and Ear
abnormalities). Patients with CHD7 loss are often diagnosed with mixed conductive and sensorineural hearing
loss; however, the pathogenic mechanisms that cause sensorineural hearing loss are not known. In the inner
ear, CHD7 is dynamically expressed in neurosensory progenitors, mesenchyme, sensory epithelium, and other
otic cell types. However, it is unclear which otic cell type(s) and what type of cis-regulatory element(s) are
perturbed in the presence of pathogenic CHD7 mutations. In addition, CHD7 has been shown to reposition
nucleosomes in vitro, yet the chromatin remodeling activity of CHD7 in vivo during otic development has not
been determined. Enrichment of CHD7 at different cis-regulatory elements is cell type dependent, and our
preliminary studies have identified CHD7 binding to the promoter of long noncoding RNA transcripts preceding
neuronal differentiation in immortalized multipotent otic progenitors (iMOPs). We hypothesize that CHD7 forms
a chromatin remodeling complex in otic neurosensory progenitors and binds to cis-regulatory elements to
regulate transcription. We will test our hypothesis using a combination of mouse genetics, single-cell
sequencing approaches, and super-resolution microscopy. Results from these studies will help identify
mechanisms underlying sensorineural hearing loss, enhance understanding of epigenetic regulation of inner
ear neurosensory cell development, and contribute knowledge to help design regenerative or restorative
therapies for the inner ear.