Pou4f3 enhancers in hearing loss treatment

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Millions of people are affected by sensorineural hearing loss caused by genetic mutations or environmental stimuli, and currently there is no curative treatment for sensorineural hearing loss. Transcription factor POU4F3 is essential for sensory hair cell differentiation, homeostasis and regeneration. During development, POU4F3 is required for ATOH1 to bind to enhancers of many hair cell genes to initiate their expression; after hearing onset, reduced transcription activity of POU4F3 due to mutations of one allele leads to hair cell death and hearing loss (DFNA15, autosomal dominant non-syndromic hearing loss 15, in human patients); and overexpression of POU4F3 in supporting cells stimulates hair cell fate conversion. However, the transcription of the Pou4f3 gene is poorly understood and there is no feasible method to regulate Pou4f3 expression from the endogenous allele to treat DFNA15 or to regenerate hair cells. In this project, we will characterize putative Pou4f3 enhancers to investigate the transcription regulatory mechanisms controlling Pou4f3 expression and utilize these putative enhancers to stimulate Pou4f3 expression in hair cells for a potential DFNA15 treatment or in supporting cells for a new strategy to regenerate hair cells. This work will further our understanding of the regulatory network governing hair cell specific gene expression, develop therapeutic treatments of DFNA15 and other forms of hearing loss associated with haploinsufficiency, and provide a new hair cell regeneration strategy with sufficient flexibility for a variety of factor combinations.