Repression of Progenitor Programs Safeguards Pancreatic Endocrine Cell Identity

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 α-cell identity, loss of δ- and γ-cell lineages, and incompletely differentiated, immature β cells. We show that ISL1 represses intermediate developmental programs during endocrine cell differentiation and facilitates chromatin transitions to drive terminal differentiation and maturation.