ISL1 controls pancreatic alpha cell fate and regulates beta cell differentiation and maturation [RNA-seq]

Glucose homeostasis is dependent on functional pancreatic α and ß cells. Mechanisms underlying generation and maturation of these endocrine cells remain unclear. Here, we unravel the molecular mode of action of ISL1 in controlling α cell fate and endocrine differentiation in the pancreas. By combining transgenic mouse models, transcriptomic and epigenomic profiling, we uncover that elimination of Isl1 results in a diabetic phenotype with a complete loss of α cells, disrupted pancreatic islet architecture, downregulation of maturation markers of ß cells, and an enrichment in an intermediate endocrine progenitor transcriptomic profile. Mechanistically, apart from the altered transcriptome of pancreatic endocrine cells, Isl1 elimination results in altered silencing H3K27me3 histone modifications in the promoter regions of the essential genes for endocrine cell differentiation. Our results thus show that ISL1 transcriptionally and epigenetically controls α cell fate competence, and ß cell maturation, suggesting that ISL1 is a critical component for generating functional α and ß cells. Together 22 samples of 100 FACS-sorted tdTomato+ endocrine cells were analyzed. 11 samples of P9 (biological replicates of 5 control and 6 mutant samples) and 11 samples of E14.5 (biological replicates of 6 control and 5 mutant samples) were analyzed separately.