HIC1 Represses Atoh1 Transcription and Hair Cell Differentiation in the Cochlea

Across species, expression of the basic helix-loop-helix transcription factor ATOH1 promotes differentiation of cochlear supporting cells to sensory hair cells required for hearing. In mammals, this process is limited to development, whereas nonmammalian vertebrates can also regenerate hair cells after injury. The mechanistic basis for this difference is not fully understood. Hypermethylated in cancer 1 (HIC1) is a transcriptional repressor known to inhibit Atoh1 in the cerebellum. We therefore investigated its potential role in cochlear hair cell differentiation. We find that Hic1 is expressed throughout the postnatal murine cochlear sensory epithelium. In cochlear organoids, Hic1 knockdown induces Atoh1 expression and promotes hair cell differentiation, while Hic1 overexpression hinders differentiation. Wild-type HIC1, but not the DNA-binding mutant C521S, suppresses activity of the Atoh1 autoregulatory enhancer and blocks its responsiveness to β-catenin activation. Our findings reveal the importance of HIC1 repression of Atoh1 in the cochlea, which may be targeted to promote hair cell regeneration.