Comprehensive analysis of aberrant alternative splicing and RNA binding proteins regulators associated with age-related sensorineural hearing loss
The mechanisms of RNA binding proteins (RBPs) regulate alternative splicing(AS) in age-related sensorineural hearing loss (SNHL) is unclear.We used RNA-seq data from the database to identify AS events and differentially expressed RNA binding proteins (DERBPs) among Control, Age8 and Age12 group in the mouse models of age-related SNHL. GO database and KEGG pathway were used to analysis the function, the co-expression relationship between regulated alternative splicing(RAS) and DERBPs were established to investigate the mechanism of RBPs regulating AS in age-related SNHL. An age-related SNHL mouse model was successfully reconstructed and cochlear tissues were obtained for experimental validation of the RNA-seq data. AS regulation significantly different in age-related SNHL. The Chronological group exhibited 198 RAS, 1012 differentially expressed genes (DEGs), and 25 DERBPs. Diseased group identified 187 RAS, 523 DEGs, and 14 DERBPs. The reconstructed animal model of age-related SNHL confirmed the enrichment of RAS in the positive regulation of GTPase activity pathway and the validated transcriptome expression of Isg15, Myom1, and Acan were found to be consistent with the trend observed in the data analysis. Besides, co-expression analyses of Isg15 and Uap1 trends were consistent with experimentally validated trends and they were negatively correlated. Isg15 may affect the mechanism of age-related SNHL by regulating Uap1, which requires further investigation. Overall design: We established age-related mouse models and employed whole transcriptome sequencing data to identify genes associated with age-related sensorineural hearing loss, including both mRNA and long non-coding RNA (lncRNA) genes.