Insights into inner ear-specific gene regulation: Epigenetics and non-coding RNAs in inner ear development and regeneration

Abstract

The vertebrate inner ear houses highly specialized sensory organs, tuned to detect and encode sound, head motion and gravity. Gene expression programs under the control of transcription factors orchestrate the formation and specialization of the non-sensory inner ear labyrinth and its sensory constituents. More recently, epigenetic factors and non-coding RNAs emerged as an additional layer of gene regulation, both in inner ear development and disease. In this review, we provide an overview on how epigenetic modifications and non-coding RNAs, in particular microRNAs (miRNAs), influence gene expression and summarize recent discoveries that highlight their critical role in the proper formation of the inner ear labyrinth and its sensory organs. Finally, we discuss recent insights into how epigenetic factors and miRNAs may facilitate, or in the case of mammals, restrict inner ear sensory hair cell regeneration.

Keywords: DNA methylation; Deafness; Hair cell regeneration; Histone modification; Inner ear development; microRNA.

Fig. 1

Schematic diagram of miRNA biogenesis and epigenetic mechanisms in the mammalian cell. Common histone PMTs such as histone methylation (me) and acetylation (ac) are indicated. DNA methylation is shown on the DNA double helix, as 5-MeC and CH₃. Gene transcription produces a pri-miRNA that is processed by Drosha to form a pre-miRNA. Exportin-5 facilitates its export to the cytoplasm, where Dicer cleaves the pre-miRNA into short double-stranded RNA. The RISC complex is activated and its catalytic component argonaute (Ago) leads to degradation of mRNA, translational suppression and deadenylation.