Modelling and modulating diabetes-associated splicing dysregulation using human stem cell-derived islets

Objective

Diabetes mellitus affects over 500 million people worldwide and arises from the progressive loss of functional insulin-producing beta cells. While transcriptional and epigenetic regulation of beta cells has been studied extensively, the role of alternative splicing, a fundamental mechanism that expands transcriptome and proteome diversity, remains poorly understood in this context. The BetaSpReg project aims to uncover how splicing regulators of the hnRNP family control beta cell development, function, and stress resilience, and to explore splice-switching oligonucleotides (SSOs) as a novel therapeutic strategy. Using human induced pluripotent stem cell-derived islets (SC-islets) and advanced CRISPR genome editing, I will generate precise knockout, inducible, and rescue models for hnRNPA2B1 and hnRNPM, two strong candidate regulators of beta cell splicing. I will combine functional assays, multi-omics profiling, and RNA immunoprecipitation followed by sequencing (RIP-seq) to define hnRNP-regulated splicing networks under basal and diabetogenic stress conditions. To increase the translational relevance, I will test SSOs targeting dysregulated splicing events in primary human islets from type 2 diabetes donors. By delivering the first mechanistic map of splicing regulation in human beta cells, BetaSpReg will expand our understanding of alternative splicing in diabetes, establish proof-of-concept for splicing modulation as therapy, and provide a foundation for RNA-based precision medicine in metabolic disease.