CUT&Tag analysis of Isl1CKO and control pancreatic endocrine cells

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.