Abstract
Hearing loss is often due to the absence or the degeneration of hair cells in the cochlea. Understanding the mechanisms regulating the generation of hair cells may therefore lead to better treatments for hearing disorders. To elucidate the transcriptional control mechanisms specifying the progenitor cells (i.e. prosensory cells) that generate the hair cells and support cells critical for hearing function, we compared chromatin accessibility using ATAC-seq in sorted prosensory cells (Sox2-EGFP+) and surrounding cells (Sox2-EGFP−) from E12, E14.5 and E16 cochlear ducts. In Sox2-EGFP+, we find greater accessibility in and near genes restricted in expression to the prosensory region of the cochlear duct including Sox2, Isl1, Eya1 and Pou4f3. Furthermore, we find significant enrichment for the consensus binding sites of Sox2, Six1 and Gata3—transcription factors required for prosensory development—in the open chromatin regions. Over 2,200 regions displayed differential accessibility with developmental time in Sox2-EGFP+ cells, with most changes in the E12-14.5 window. Open chromatin regions detected in Sox2-EGFP+ cells map to over 48,000 orthologous regions in the human genome that include regions in genes linked to deafness. Our results reveal a dynamic landscape of open chromatin in prosensory cells with potential implications for cochlear development and disease.
Highlights
Hearing is mediated by a specialized sensory epithelium, the organ of Corti, within the cochlea of the inner ear
To selectively characterize the accessible chromatin in prosensory cells in the developing cochlea, we carried out ATAC-seq on FACS isolated EGFP+ cells from Sox2-EGFP mice, a strain having EGFP knocked-into the Sox[2] coding region[59]
Similar to endogenous Sox[2] expression, the highest level of Sox2-EGFP immunofluorescence is evident in the prosensory cells of the cochlear duct as well as the glia of the spiral ganglion in the E12, E14 and E16 cochleae (Fig. 1)
Summary
Hearing is mediated by a specialized sensory epithelium, the organ of Corti, within the cochlea of the inner ear. To better understand the interactions among these signaling molecules and transcriptional regulation of cochlear development, we used ATAC-seq to map the open chromatin regions in cells of the prosensory domain (Sox2-EGFP+) as well as the surrounding nonsensory cells (Sox2-EGFP−) isolated from the embryonic mouse cochlear duct. Open chromatin regions in Sox2-EGFPhigh+ cells of the embryonic cochlear duct map to genes and gene-regulatory regions including known otic enhancers.
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