Inhibition of Histone Methyltransferase G9a Attenuates Noise-Induced Cochlear Synaptopathy and Hearing Loss

Abstract

Posttranslational modification of histones alters their interaction with DNA and nuclear proteins, influencing gene expression and cell fate. In this study, we investigated the effect of G9a (KMT1C, EHMT2), a major histone lysine methyltransferase encoded by the human EHMT2 gene and responsible for histone H3 lysine 9 dimethylation (H3K9me2) on noiseinduced permanent hearing loss (NIHL) in adult CBA/J mice. The conditions of noise exposure used in this study led to losses of cochlear synapses and outer hair cells (OHCs) and permanent auditory threshold shifts. Inhibition of G9a with its specific inhibitor BIX 01294 or with siRNA significantly attenuated these pathological features. Treatment with BIX 01294 also prevented the noise-induced decrease of KCNQ4 immunolabeling in OHCs. Additionally, G9a was increased in cochlear cells, including both outer and inner sensory hair cells, some spiral ganglion neurons (SGNs), and marginal cells, 1 h after the completion of the noise exposure. Also subsequent to noise exposure, immunoreactivity for H3K9me2 appeared in some nuclei of OHCs following a high-to-low frequency gradient with more labeled OHCs in the 45-kHz than the 32-kHz region, as well as in the marginal cells and in some SGNs of the basal turn. These findings suggest that epigenetic modifications of H3K9me2 are involved in NIHL and that pharmacological targeting of G9a may offer a strategy for protection against cochlear synaptopathy and NIHL.

The DNA methylation inhibitor RG108 protects against noise-induced hearing loss

“…A previous study by our research group reported that neomycin-induced elevations of histone methyltransferase G9a and H3K9me2 amounts are associated with aminoglycoside-induced hair cell loss, and pharmacological targeting of G9a with BIX 01294 could prevent damage to inner ear hair cells (Yu et al 2013). Delivery of G9a siRNA in vivo 72 h prior to noise exposure also significantly reduced ABR threshold shifts and ameliorated noise-induced permanent hearing loss (Xiong et al 2019). Additionally, a histone deacetylase inhibitor, suberoylanilide hydroxamic acid, was shown to protect outer hair cells from noise-induced damage, hence, raising the possibility that epigenetic regulation may be a potential therapeutic strategy to prevent hearing loss (Wen et al 2015).…”

Noise-induced loss of sensory hair cells is mediated by ROS/AMPKα pathway

“…However, exposure to 100 dB SPL for 2 h induces PTS with losses of both OHCs and IHCs in a fashion similar to that of exposure to 106 dB SPL in the same strain of mice at the age of 12 weeks [13,36,42]. Additionally, we were unable to induce PTS with loss of OHCs only (non IHC loss) when using 8-week-old CBA/J mice without dietary enrichments, although we have previously characterized such noise conditions with same strain mice at the age of 12 weeks [51,53]. Regardless of whether octave band (with a frequency spectrum from 8–16 kHz) or broadband noise exposure (with a frequency spectrum from 2–20 kHz) is used with mice at either age (8 or 12 weeks), noise-induced loss of sensory hair cells follows a base-to-apex gradient beginning in the basal turn [13,51,54].…”

Antisense Oligonucleotides for the Treatment of Inner Ear Dysfunction

“…For the treatment of or protection against hearing loss, a number of different RNAi strategies differing in RNA targets, delivery modalities, and types of siRNA/miRNA molecules have shown efficacy in animal models. These include but are not limited to RNA approaches involving the knockdown of mRNA encoding toxic, gain-of-function proteins [26,43] or modulation of gene pathways that limit regeneration or protect against noise-induced hearing loss [44][45][46] or cisplatin-induced ototoxicity [47][48][49]. In most cases reported, unformulated siRNAs were delivered via trans-tympanic injection to the middle ear prior to the induction of hearing and hair cell damage, which results in modest protection from hearing loss.…”