ReviewRecent advancements in understanding the role of epigenetics in the auditory system
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.
Section snippets
Functional anatomy and physiology of inner ear
In order to understand how epigenetic modifications affect the hair cells in cochlea and lead to SNHL, it is first crucial to comprehend the anatomy, physiology, and development of the inner ear. In the mammalian ear, vibrations are converted into electrical impulses by cochlear sensory cells and transmitted to the brain via the cochlear nerve, where they are decoded (Areias et al., 2016) (Fig. 1). The auditory cortex in the brain can then properly interpret these impulses for interaction with
DNA methylation as an epigenetic modifier
The epigenetic regulations that affect the inner ear primarily involve DNA methylation (Zhou and Hu, 2016, Roellig and Bronner, 2016, Chen et al., 2017). While various types of DNA methylation exist, the most common form is methylation of the fifth carbon of a cytosine ring. The covalent addition of the methyl group changes cytosine into 5-methylcytosine, or 5-mC. These bulky methyl groups protrude from strands of DNA, in some cases blocking the binding of transcription factors to promoters and
Histone acetylation and deacetylation in facilitating epigenetic alterations
Several studies have emerged to demonstrate the relationship between histone acetylation, deacetylation, and hearing loss. Alteration of expression and activity of histone deacetylases (HDACs) has been associated with SNHL (Stew et al., 2012, Hou et al., 2016), NIHL (Wen et al., 2015; Chen et al., 2016) and ototoxic deafness (Wang et al., 2015). An age-related reduction of acetylated histone H3 was observed in the spiral ganglion cells and the organ of Corti of mice (Watanabe and Bloch, 2013).
Histone methylation and hearing loss
In addition to histone acetylation and deacetylation, studies have shown a correlation between hearing loss and the epigenetic mechanisms surrounding histone methylation. Histone methylation occurs when methyl groups are added to amino acid groups on the histone tails by histone methyltransferases (Kim et al., 2017, Patel, 2016). Residues can be mono, di, or trimethylated (Teske and Hadden, 2017). Methyltransferase enzymes transfer methyl groups mainly to lysine or arginine on H3 and H4
Future perspectives/technological advancements
The field of epigenetics is expanding rapidly, and potentially can enhance our understanding about the mechanisms that affect the inner ear and hearing loss. New technologies have consequently been developed and are consistently emerging to investigate the epigenetics of the inner ear, though epigenetic connections are complex and require various methods to deconstruct and understand. The first important technological advancement that can be used to further enhance our understanding about the
Understanding the epigenetic mechanisms controlling hair cell regeneration in the organ of Corti
Embryogenesis involves the progressive restriction of cell fate from the totipotent fertilized egg to the specialized cells that make up adult tissues. In developing systems, cellular differentiation occurs through a branching, iterative process in which a hierarchy of transcription factors interact specifically with regulatory DNA sequence elements such as enhancers and promoters, to bring about the precise transcriptional events needed at each stage. Although in early embryos many cell types
Conclusions
Though minimal data exist regarding epigenetic modifications and their mechanisms influencing the inner ear, research has begun to provide an understanding of these modifications in the auditory system. Epigenetic factors such as DNA methylation and histone modification have been proven to work in tandem to regulate inner ear function, and afferent changes to these mechanisms often result in deafness. With regard to DNA methylation, strides have been made in recognizing that DNMT1 and DNMT3A
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgements
This work was supported by National Institute of Health/National Institute on Deafness and Other Communication Disorders (R01-DC005575, R01DC017264, and R01 DC012115 to XZL; XZL; T32 DC015995 to XZL for resident NE, K08 DC017508 to CTD). We are thankful to Dr. Valerie Gramling for critical reading of the manuscript. Nicole Bencie is a recipient of the 2017 LINK/SEW Award from Brown University.
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