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Differential chromatin accessibility, gene expression and mRNA splicing between developing cochlear inner and outer hair cells [ATAC-Seq]

ABSTRACT: The mammalian cochlea has two types of low abundance and highly specialized inner (IHC) and outer (OHC) mechanosensory hair cells. Their malfunction or death are common causes of congenital and acquired deafness. We separately collected developing IHCs and OHCs to identify their mRNAs and chromatin state. We examined their transcriptomes by RNA-seq to reveal differences in gene expression and alternative mRNA splicing. We examined their chromatin conformation by ATAC-seq to reveal open vs closed promoter and enhancer elements. Combining both approaches we find that developing IHCs and OHCs have differentially accessible promoters in differentially expressed genes, differ in both levels of gene expression, extent of mRNA splicing and transcription start sites, and utilize unique promoters and mRNA isoforms absent in other cell types. We provide a resource for the identification of promoter and mRNA isoforms of every gene expressed by IHCs or OHCs.

ORGANISM(S): Mus musculus

PROVIDER: GSE288376 | GEO | 2025/09/08

REPOSITORIES: GEO

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Project description:The mouse auditory organ cochlea contains two types of sound receptors: inner hair cells (IHCs) and outer hair cells (OHCs). Tbx2 is expressed in IHCs but repressed in OHCs, and neonatal OHCs that misexpress Tbx2 transdifferentiate into IHC-like cells. However, the extent of this switch from OHCs to IHC-like cells and the underlying molecular mechanism remain poorly understood. Furthermore, whether Tbx2 can transform fully mature adult OHCs into IHC-like cells is unknown. Here, our single-cell transcriptomic analysis revealed that in neonatal OHCs misexpressing Tbx2, 85.6% of IHC genes, including Slc17a8, are upregulated, but only 38.6% of OHC genes, including Ikzf2 and Slc26a5, are downregulated. This suggests that Tbx2 cannot fully reprogram neonatal OHCs into IHCs. Moreover, Tbx2 also failed to completely reprogram cochlear progenitors into IHCs. Lastly, restoring Ikzf2 expression alleviated the abnormalities detected in Tbx2+ OHCs, which supports the notion that Ikzf2 repression by Tbx2 contributes to the transdifferentiation of OHCs into IHC-like cells. Our study evaluates the effects of ectopic Tbx2 expression on OHC lineage development at distinct stages of either male or female mice and provides molecular insights into how Tbx2 disrupts the gene-expression profile of OHCs. This research also lays the groundwork for future studies on OHC regeneration.Significance Statement Elucidation of the molecular and genetic mechanisms governing the determination and stability of cochlear inner hair cells (IHCs) and outer hair cells (OHCs) should provide valuable insights into the regeneration of damaged IHCs and OHCs. Here, we conditionally overexpress Tbx2 in vivo in cochlear sensory progenitors, neonatal OHCs, or adult OHCs. Our results show that Tbx2 overexpression alone can partially destabilize the OHC fate but cannot fully convert OHCs into IHCs. Specifically, we demonstrate that Ikzf2 repression due to Tbx2 overexpression is one of the key pathways disrupting the OHC fate.

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Differential chromatin accessibility, gene expression and mRNA splicing between developing cochlear inner and outer hair cells [ATAC-Seq]

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