Recent advancements in understanding the role of epigenetics in the auditory system

Abstract

Sensorineural deafness in mammals is most commonly caused by damage to inner ear sensory epithelia, or hair cells, and can be attributed to genetic and environmental causes. After undergoing trauma, many non-mammalian organisms, including reptiles, birds, and zebrafish, are capable of regenerating damaged hair cells. Mammals, however, are not capable of regenerating damaged inner ear sensory epithelia, so that hair cell damage is permanent and can lead to hearing loss. The field of epigenetics, which is the study of various phenotypic changes caused by modification of genetic expression rather than alteration of DNA sequence, has seen numerous developments in uncovering biological mechanisms of gene expression and creating various medical treatments. However, there is a lack of information on the precise contribution of epigenetic modifications in the auditory system, specifically regarding their correlation with development of inner ear (cochlea) and consequent hearing impairment. Current studies have suggested that epigenetic modifications influence differentiation, development, and protection of auditory hair cells in cochlea, and can lead to hair cell degeneration. The objective of this article is to review the existing literature and discuss the advancements made in understanding epigenetic modifications of inner ear sensory epithelial cells. The analysis of the emerging epigenetic mechanisms related to inner ear sensory epithelial cells development, differentiation, protection, and regeneration will pave the way to develop novel therapeutic strategies for hearing loss.

Introduction

Hearing loss is a critical medical and public health issue (Blazer, 2020, Punch et al., 2019, Mormer et al., 2017, Korver et al., 2017, Nirmalasari et al., 2017, Imam and Hannan, 2017). Approximately 37.5 million American adults (15%) aged 18 and over have hearing impairment (Blackwell et al., 2014, Mitchell and Karchmer, 2004). Indeed, the number of individuals over the age of 20 with hearing loss is expected to increase from 44.11 million (15%) in 2020 to 73.5 million (22%) in 2060, requiring substantially more attentive care and specialized treatment modalities (Goman et al., 2017). The National Academies of Sciences, Engineering and Medicine expects hearing loss to become the fifth most common disability in the world. The objective of this article is to review the recent advancements in understanding the role of epigenetics in the auditory system. Better understanding of how epigenetics regulates inner ear development and its role in hearing impairment will open up avenues to develop therapeutic strategies for hearing loss.

Hearing loss is a significant medical burden for society. Depression, decline in physical functioning, cognitive impairment and hospitalization have been associated with age-related hearing impairments in older individuals (Nirmalasari et al., 2017, Nieman and Lin, 2017, Agmon et al., 2017). The sound transmits from outer to inner ear through the middle ear and any obstruction along the auditory pathway can lead to hearing loss (Fig. 1). There are two main types of hearing loss - Sensorineural and Conductive (Fig. 1) (Shearer et al., 1999). Both types can also exist simultaneously causing a 'mixed' hearing loss (Fig. 1). More rarely, hearing loss can result from auditory cortex damage in the central nervous system (Korver et al., 2017). Conductive hearing loss occurs when the transmission of sound from outer to inner ear is obstructed (Subramanian et al., 2017). Sensorineural hearing loss (SNHL) occurs from damage to the cochlea leading to the inability of the inner ear to transduce sound waves to the brain, and accounts for 90% of hearing loss (Coffey et al., 2017). Mixed hearing loss is the result of a combination of both conductive and sensorineural hearing loss—where sensorineural loss can occur from trauma to the inner ear or nerve to the brain.

Although various factors are involved in hearing loss, genetics is the most common etiology (Koohiyan, 2020, Wells et al., 2020, Yan et al., 2017, Cai et al., 2017, Tang et al., 2017, Rehman et al., 2017, Xia et al., 2017). According to the American Speech and Language Association, genetic abnormalities are the number one cause of SNHL and account for 50% to 60% of all cases (Paludetti et al., 2012). In the absence of pre-existing conditions, over 150 loci have been linked to SNHL by affecting inner ear development and function (NIH, 2017; http://hereditaryhearingloss.org/). The mutations in genes located on these loci most commonly result in degeneration of inner ear sensory epithelia, or hair cells in the inner ear organ of Corti, the organ that contains cells vital to an individual’s ability to hear (Kremer, 2019, Brigande, 2017, Mittal et al., 2017).

Alongside genetics, the closely related field of epigenetics has made strides in uncovering mechanisms that improve the development of therapies in a variety of medical fields (Boison and Rho, 2020, Obri et al., 2020, Shamsi et al., 2017). Epigenetics refers to the field of study that observes various phenotypic changes that result from genetic expression rather than changes in the genetic code (Ajonijebu et al., 2017). Epigenetic mechanisms, working alongside with the DNA template to modulate gene expression programs that determine cell-type identities and states, include DNA methylation, nucleosome positioning, histone modifications, chromatin structure, non-histone binding proteins, and non-coding RNAs (ncRNAs) (Han and He, 2016). This article focuses primarily on DNA methylation and histone modifications as these two epigenetic modifications have been shown to potentially play an essential role in various types of hearing loss. DNA methylation involves the transfer of a methyl group onto cytosine or adenine nucleotides via a DNA methyltransferase (DNMT) enzyme family (Hyun et al., 2017, Wu et al., 2017, Kernohan et al., 2016). The addition of these methyl groups in promoter sequences is usually associated with silencing gene expression. Besides DNA methylation, there are three main types of histone modifications that seem to play a role in hearing loss, namely histone methylation, histone acetylation, and histone deacetylation. Histone methylation occurs when methyl groups are added to amino acid groups on the histone tails using histone methyltransferases (Kim et al., 2017, Patel, 2016). Histone acetylation and deacetylation describes the addition or removal of acetyl groups mainly on histones 3 and 4 by histone acetyltransferases (HATs) and histone deacetylases (HDACs). Histone post-translational modifications give rise to structural responses at the chromatin level, such as gene expression regulation and silencing (Bowman et al., 2014). Specific post-translational modifications can facilitate binding of transcriptional factors as well as directly modulate the strength of the interactions between the histone octamer and nucleosomal DNA, impacting higher-order chromatin structures (North et al 2012). All of these epigenetic changes have been shown to affect the cochlea and can be involved in various forms of hearing loss.

Currently, inroads into epigenetic mechanisms and their influences on the inner ear are just beginning. While the exact biological mechanisms and other specificities behind epigenetics in the inner ear remain only minimally understood, it is clear that a strong correlation exists behind epigenetic modifications, the inner ear, and various forms of SNHL (Seker Yildiz et al., 2017). Epigenetic modifications have been corelated with hearing impairment in humans (Table 1) suggesting their critical roles in the auditory system.