Wu, WentingSyed, FarooqSimpson, EdwardLee, Chih-ChunLiu, JingChang, GarrickDong, ChuanpengSeitz, ClaytonEizirik, Decio L.Mirmira, Raghavendra G.Liu, YunlongEvans-Molina, Carmella2024-04-292024-04-292021Wu W, Syed F, Simpson E, et al. Impact of Proinflammatory Cytokines on Alternative Splicing Patterns in Human Islets. Diabetes. 2021;71(1):116-127. doi:10.2337/db20-0847https://hdl.handle.net/1805/40312Alternative splicing (AS) within the β-cell has been proposed as one potential pathway that may exacerbate autoimmunity and unveil novel immunogenic epitopes in type 1 diabetes (T1D). We used a computational strategy to prioritize pathogenic splicing events in human islets treated with interleukin-1β plus interferon-γ 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. In total, 969 AS events were identified in cytokine-treated islets, with a majority (44.8%) involving a skipped exon. ExonImpact identified 129 events predicted to affect protein structure. AS occurred with high frequency in MHC class II–related mRNAs, and targeted quantitative PCR validated reduced inclusion of exon 5 in the MHC class II gene HLA-DMB. Single-molecule RNA fluorescence in situ hybridization confirmed increased HLA-DMB splicing in β-cells from human donors with established T1D and autoantibody positivity. Serine/arginine-rich splicing factor 2 was implicated in 37.2% of potentially pathogenic events, including exon 5 exclusion in HLA-DMB. Together, these data suggest that dynamic control of AS plays a role in the β-cell response to inflammatory signals during T1D evolution.en-USPublisher PolicyAlternative splicing (AS)β-cellType 1 diabetes (T1D)Pathogenic splicingArticle