SIX1 is required for adult cochlear sensory epithelium homeostasis and auditory function

To uncover the underlying regulatory circuitry, we mapped genome-wide SIX1 occupancy in the mature cochlea. SIX1 binds DNA elements/enhancers near genes involved in cell adhesion, junctional integrity, actin dynamics, hair-bundle assembly, ion-channel, mechanotransduction, and cell survival, many of which are frequently mutated in hereditary deafness. Motif analysis showed that these SIX1-bound sites retain the core co-motifs found in SIX1 peaks in embryonic cochlea, suggesting reuse of embryonic cofactors.

Notably, SIX1 occupies an intronic enhancer of Srf and physically interacts with SRF protein, positioning SIX1 atop an SRF-centered actin-cytoskeletal circuit crucial for bundle stability. Together, our findings redefine SIX1 as a lifelong regulator of cochlear homeostasis and reveal its downstream networks that maintain the adult auditory sensory epithelium.