Whole-Genome DNA Methylation Analysis in Age-Related Hearing Loss

Presbycusis, also known as age-related hearing loss (ARHL), is the most frequent sensory disability affecting elderly adults worldwide. ARHL is characterized by bilateral, progressive, sensorineural hearing loss that is more pronounced at a high frequency. Conventional factors associated with ARHL include diabetes, hypertension, and a family history of hearing loss. The severity of hearing impairment varies between individuals. The defined causative molecular pathogenesis for ARHL is unknown, thus the identification of underlying pathogenic mechanisms involved in ARHL is imperative for the development of effective therapeutic approaches. Epigenetics is the study of phenotypic changes caused by the modification of gene expression rather than the alteration of a DNA sequence. While it is hypothesized that ARHL could result from undiscovered epigenetic susceptibility, there is a shortage of information on the role that epigenetic modification plays in ARHL. Here we present an investigation on the involvement of DNA methylation in ARHL.

Clinical, audiometric and DNA testing, and high-throughput methylation pattern screening were undertaken for ARHL patients and matched control subjects. Our results demonstrate a strong correlation between patients' hearing measurements and methylation at CpG sites cg1140494 (ESPN) and cg27224823 (TNFRSF25). We identified 136 differentially methylated CpGs that were shared between a high and low audiometric frequency in the patient's cohort. CpG cites in hearing loss candidate genes, KCNQ1, TMEM43, GSTM1, TCF25, and GSR, were found to be highly methylated in presbycusis patients as compared to the controls. A methylation polymerase chain reaction (PCR) assay was used to confirm methylation levels at a specific gene locus in ARHL patients and controls.

Altered DNA methylation and its impact on gene expression has been implicated in many biological processes. By interrogating the methylation status across the genome of both hearing loss patients and those with normal hearing, our study can help to establish an association between the audiometric patterns and methylation status in ARHL, yielding new avenues for the identification of potential candidate genes for hearing loss.