AUF1 modulates apoptosis via regulating transcription and alternative splicing of immune response genes in auditory hair cells

Abstract Background: AU-rich element RNA-binding factor 1 (AUF1) is a multifunctional RNA binding proteins (RBPs) in post-transcriptional gene regulation. However, it remains unclear whether or not AUF1 has a function in the regulation of inflammation and apoptosis as a splicing factor in presbycusis and auditory hair cells. Methods: In this study, RNA-seq was used to analyze the global transcript level and alternative splicing in AUF1 siRNA-treated HEI-OC1 cells (siAUF1) and control cells. Integration analysis was carried out using published transcriptome and AUF1-RNA interactome datasets. Results: SiAUF1 was found to promote the level of apoptosis in HEI-OC1 cells. The RNA-seq results indicated the extensive regulation of the expression of hundreds of genes by AUF1 knocked down cells. The genes down-regulated by siAUF1 were significantly involved in immune responses and cellular apoptosis. AUF1 regulated the alternative splicing of genes, such as FASTK, MAP4, and hnRNPDL, that are involved in mitochondrial functioning and cellular apoptosis. Furthermore, the published transcriptomic data of aging mice demonstrated that the expression of AUF1 and immune response were highly exhibited in aging animals. Moreover, RBMS3 was also found to be an important gene target of AUF1 to modulate apoptosis. Conclusion: To our knowledge, this is the first investigation of its kind that has described the transcriptome-wide analysis of AUF1-regulated expression and alternative splicing profiles and has demonstrated the possible mechanisms of AUF1 regulating immune response, apoptosis, and alternative splicing, which could aid future researches on cellular biology and contribute to the deciphering of the aging process and presbycusis.