Repression of Progenitor Programs Safeguards Pancreatic Endocrine Cell Identity

Pancreatic endocrine cells regulate glucose homeostasis and energy metabolism in response to nutrients. All pancreatic endocrine cells originate from a common progenitor population through multiple coordinated cell fate decisions. ISL1 is a key lineage-determining transcription factor, but its role in endocrine cell identity, differentiation, and maturation is insufficiently characterized. By integrating single-cell RNA profiling with H3K27ac and H3K27me3 histone modification analyses, we identified a reshaped transcriptome and epigenetic landscape in Isl1-deficient endocrine cells leading to altered -cell identity, loss of - and -cell lineages, and incompletely differentiated, immature cells. We show that ISL1 represses intermediate developmental programs during endocrine cell differentiation and facilitates chromatin transitions to drive terminal differentiation and maturation. These findings provide insights into how combinatorial transcription factor-epigenome interactions activate and repress transcriptional programs driving cell fate acquisition, differentiation, and maturation during endocrine pancreas development. We created conditional knockout mouse model using Cre-loxP system. Isl1CKO mutants carry genotype Neurod1 Cre/+; Isl1 f/f and mice with genotype Neurod1 Cre/+; Isl1f/+ do not show any phenotype and are used as controls. TdTomato fluorescent protein is used as reporter. 1 month (M1) mice were sacrificed and pancreases were dissected. 3 samples from each genotype were pooled together. FACSed tdTomato+ cells were loaded to 10x Chromium Next GEM Single cell 3' Reagents kit v.3.1.