| Autor: |
Raghavendra G. Mirmira, Edward Simpson, Farooq Syed, Yunlong Liu, Chih-Chun Lee, Wenting Wu, Chuanpeng Dong, Garrick Chang, Jing Liu, Carmella Evans-Molina, Clayton Seitz, Decio L. Eizirik |
| Rok vydání: |
2021 |
| Předmět: |
|
| Zdroj: |
Diabetes |
| ISSN: |
0012-1797 |
| Popis: |
Alternative 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. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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