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The Impact of Pro-Inflammatory Cytokines on Alternative Splicing Patterns in Human Islets
figure
posted on 2021-10-25, 22:26 authored by Wenting Wu, Farooq Syed, Edward Simpson, Chih-Chun Lee, Jing Liu, Garrick Chang, Chuanpeng Dong, Clayton Seitz, Decio L. Eizirik, Raghavendra G. Mirmira, Yunlong Liu, Carmella Evans-MolinaAlternative 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 employed a
computational strategy to prioritize pathogenic splicing events in human islets
treated with IL-1β + IFN-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 the
majority (44.8%) involving a skipped exon.
ExonImpact identified 129 events predicted to impact protein structure. AS 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. Single-molecule RNA FISH confirmed increased
HLA-DMB splicing in pancreatic sections from human donors with established T1D
and autoantibody positivity. Serine and Arginine Rich Splicing Factor 2 was
implicated in 37.2% of potentially pathogenic events, including Exon5 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.