Associations of genetic variation in E3 SUMO-protein ligase CBX4 with noise-induced hearing loss

Abstract

Abstract Noise-induced hearing loss (NIHL) is a multifactorial disease caused by environmental, genetic and epigenetic variables. SUMOylation is a post-translational modification that regulates biological processes. The objective of this study was to determine the link between genetic variation in the chromobox 4 (CBX4) and the risk of NIHL. This study applied a case–control design with 588 cases and 582 controls, and the sample was predominantly male (93.76%). The T allele of CBX4 rs1285250 was found to be significantly linked with NIHL (P = 0.002) and showed strong associations in both the codominant and recessive models (TT versus CC, P = 0.005; TT/TC versus CC, P = 0.009). By constructing a mouse model of hearing loss because of noise exposure, changes in hearing thresholds were observed in noise-exposed mice, along with a decrease in the number of cochlear hair cells. Furthermore, noise promotes cochlear hair cell apoptosis by inducing SP1/CBX4 pathway activation. Further functional studies demonstrated that SP1 has an influence on the promoter activity of the CBX4 rs1285250 intron, with the promoter activity of the T allele being higher than that of the C allele. Knockdown of transcription factor SP1 reduced the expression of CBX4 expression and simultaneously reduced apoptosis in HEI-OC1 cells. Together, our findings have shown that CBX4 genetic polymorphism rs1285250 T-allele was associated with increased risk of NIHL and might be used as biomarkers for male workers exposed to noise. Furthermore, we speculate that the CBX4 of rs1285250 T-allele leads to a stronger potential enhancer activity from a predicted gain of stronger SP1 binding.