SoxC transcription factors shape the epigenetic landscape to establish competence for sensory differentiation in the mammalian organ of Corti

Understanding the molecular basis of competence acquisition by the lineage-specific progenitor cells can provide mechanistic insights into tissue development and regeneration. The sensory epithelium of the inner ear represents a convenient model to study this process, as only two cell types – the mechanosensory hair cells and their associated supporting cells – are specified from a single pool of progenitors in this lineage. Here we show that competence to respond to Atoh1, a transcriptional master regulator both necessary and sufficient for induction of mechanosensory hair cells, is established in the organ of Corti progenitor cells between E12.0 and 13.5. The transition to the competent state is rapid and is associated with extensive remodeling of the epigenetic landscape controlled by the SoxC group of transcription factors. Conditional loss of Sox4 and Sox11 – the two homologous family members transiently expressed in the inner ear at the time of competence establishment – blocks the ability of sensory progenitors to differentiate into hair cells. Mechanistically, we show that Sox4 binds to and establishes accessibility of early sensory lineage-specific regulatory elements, including ones associated with Atoh1 itself and its direct downstream targets. Consistent with these observations, overexpression of Sox4 or Sox11 prior to developmental establishment of competence precociously induces hair cell differentiation in the cochlear progenitors. Further, reintroducing Sox4 or Sox11 expression restores the ability of postnatal supporting cells to differentiate as hair cells in vitro and in vivo. Our findings demonstrate the pivotal role of SoxC family members as agents of epigenetic and transcriptional changes necessary for establishing competence for sensory receptor differentiation in the inner ear. 1. Cochlear duct epithelia from E13.5 wildtype and SoxC conditional double knockout animals were collected and analyzed using scRNA sequencing (10x); 2. ATAC-seq (Assay for Transposase-Accessible Chromatin using sequencing) for cochlear duct epithelia from E13.5 wildtype and SoxC conditional double knockout animals; 3. Cut & Run ChIP-seq (Chromatin immunoprecipitation DNA-sequencing) for Sox4 transcription factor in FACS sorted E13.5 p27kip1 positive cochlea progenitor cells