CUT&Tag analysis of Isl1CKO and control pancreatic endocrine cells

Pancreatic endocrine cells regulate glucose homeostasis and energy metabolism in response to nutrients. All endocrine lineages arise from a common progenitor pool through sequential and coordinated cell fate decisions. The homeodomain protein ISL1 functions as a key-lineage determining transcription factor; however, its role in establishing endocrine cell identity and driving terminal maturation remains incompletely characterized. By integrating single-cell transcriptomics with H3K27ac and H3K27me3 chromatin profiling, we uncover a reshaped transcriptomic and epigenetic landscape in Isl1-deficient endocrine cells. Loss of Isl1 disrupts α-cell identity, ablates δ- and γ-cell lineages, and results in the persistence of immature, incompletely differentiated β cells in postnatal and adult islets. Longitudinal single-cell profiling revealed that Isl1CKO endocrine cells maintain aberrant differentiation states, exhibit impaired β-cell function, activate diabetes- and stress-associated pathways, and display sex-specific responses linked to disease progression. Mechanistically, ISL1 represses intermediate developmental programs and promotes chromatin remodeling required for terminal differentiation. These findings reveal how interactions between transcription factors and the epigenome coordinate the activation and repression of gene regulatory programs that govern cell fate, and functional maturation in the endocrine pancreas.