The Impact of Pro-Inflammatory Cytokines on Alternative Splicing Patterns in Human Islets

Alternative splicing (AS) within the ß cell has been proposed as one potential pathway that may exacerbate autoimmunity and unveil novel immunogenic epitopes in type 1 diabetes (T1D). We employed a computational strategy to prioritize pathogenic splicing events in human islets treated with IL-1ß + IFN-? as an ex vivo model of T1D and coupled this analysis with a k-mer based approach to predict RNA binding proteins involved in AS events. In total, 969 AS events were identified in cytokine-treated islets, with the majority (44.8%) involving a skipped exon. AS events occurred with high frequency in MHC Class II-related mRNAs, and targeted qPCR validated reduced inclusion of Exon5 in the MHC Class II gene HLA-DMB, while RNA FISH confirmed HLA-DMB splicing in pancreatic sections from human T1D donors. Together, these data suggest that dynamic control of AS plays a role in the ß cell response to inflammatory signals during T1D evolution. Overall design: Examination of cytokines impacts on alternative splicing patterns in human islets.