Epigenetic regulation in the inner ear and its potential roles in development, protection, and regeneration

Abstract

The burgeoning field of epigenetics is beginning to make a significant impact on our understanding of tissue development, maintenance, and function. Epigenetic mechanisms regulate the structure and activity of the genome in response to intracellular and environmental cues that direct cell-type specific gene networks. The inner ear is comprised of highly specialized cell types with identical genomes that originate from a single totipotent zygote. During inner ear development specific combinations of transcription factors and epigenetic modifiers must function in a coordinated manner to establish and maintain cellular identity. These epigenetic regulatory mechanisms contribute to the maintenance of distinct chromatin states and cell-type specific gene expression patterns. In this review, we highlight emerging paradigms for epigenetic modifications related to inner ear development, and how epigenetics may have a significant role in hearing loss, protection, and regeneration.

Keywords: DNA methylation; auditory; cellular reprogramming; hair cells; histone acetylation; histone deacetylase inhibitors; histone methylation; ototoxicity.

Figure 1

Cartoon diagram indicates potential sites of modification at specific residues along the histones tail. The tails of histone H3 and H4 have the largest number of potential modification sites including lysine (K)-specific methylation and acetylation sites and arginine (R)-specific methylation sites. The tail of histone H3 is subject to both repressive lysine (K)-specific methylation marks (K9 and K27) as well as activating lysine (K)-specific methylation marks (K4, K36, and K79).

Figure 2

Chromatin state. Cartoon diagram depicting the open relaxed chromatin of an actively transcribed gene (upper portion), compared to the nucleosome dense compacted chromatin associated with a silenced gene (bottom portion). HMT—histone methyltransferase, HAT—histone acetyltransferase, TBP—TATA-binding protein, TAF—TBP-associated factors, TF—transcription factor, HDAC—histone deacetylase, KDM—lysine (K)-specific demethylase, DNMT—DNA methyltransferase, MBD—methyl-CpG-binding domain.

Figure 3

Chromatin modifications are distributed in specific gene regulatory regions. (A) The normal distribution of DNA methylation, DNA hydroxymethylation, and histone marks in the enhancer, promoter, and gene body of actively transcribed genes. Actively transcribed genes carry typically have chromatin modifications within the gene body to facilitate transcription initiation and elongation. (B) Common chromatin modifications found in the enhancer, promoter, and gene body of silenced genes. (C) Bivalent/poised genes have both activating and silencing chromatin modifications to facilitate rapid changes in gene expression during development.