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. In contrast to non-mammalian vertebrates, adult mammals lack the ability to regenerate inner ear mechano-sensory hair cells. Finally, we discuss recent insights into how epigenetic factors and miRNAs may facilitate, or in the case of mammals, restrict sensory hair cell regeneration.

Sox2 haploinsufficiency primes regeneration and Wnt responsiveness in the mouse cochlea

“…Another important consideration is the largely unknown network of transcription factors that act in concert with Sox2 and Hes5 in the neonatal and mature cochlea. Moreover, gene silencing by epigenetic factors occurs as the cochlea develops and matures (78), thus a more comprehensive investigation in these areas, including further study of the roles of Hes5, should be of interest and may help guide future therapy using Sox2 and Wnt signaling to regenerate the mature cochlea.…”

Therapeutic Potential of Wnt and Notch Signaling and Epigenetic Regulation in Mammalian Sensory Hair Cell Regeneration

“… 64 In addition to modifications on DNA and histone proteins, gene expression is also regulated by non-coding RNAs and they play a significant role in the capacity for hair cell regeneration. 65 …”

Outlook and future of inner ear therapy

“…Recent advances in understanding epigenetic changes in chromatin in general (Teschendorff et al, 2017) and in the inner ear (Doetzlhofer et al, 2017; Layman et al, 2014) increase and enhance the arsenal of possibilities for therapy, as seen by recent data on the protective effects of chromatin remodeling (Chen et al, 2009; Chen et al, 2016; He et al, 2015). Future ability to reverse epigenetic modifications could enhance the responsiveness of cells to exogenous reagents by revealing desirable binding sites on the chromatin.…”