ISL1 Restricts Progenitor Programs and Promotes β-Cell Maturation, Revealing Sex Differences in Diabetes Progression

Pancreatic islet cells differentiate from a common progenitor pool through tightly regulated transcriptional and epigenetic programs. ISL1, a LIM homeodomain transcription factor, is essential for islet development, but its molecular functions remain poorly defined. Here, we demonstrate that ISL1 is critical for maintaining endocrine cell identity and enabling terminal differentiation, particularly of α- and β-cells. Using conditional Isl1 deletion in endocrine precursors, combined with single-cell RNA sequencing and chromatin profiling (H3K27ac and H3K27me3), we reveal disruption of the transcriptional and epigenetic landscape in Isl1-deficient islets. Loss of Isl1 results in the failure to establish α-cell identity, loss of δ- and γ-cell lineages, and the persistence of immature β-cells with impaired functional profiles in Isl1CKO mice. Longitudinal single-cell analysis shows that Isl1CKO endocrine cells exhibit sustained progenitor-like states and defective β-cell maturation. These defects are accompanied by activation of stress and diabetes-associated transcriptional programs, along with sex-specific responses that may influence disease onset and progression. Mechanistically, ISL1 represses intermediate progenitor programs and facilitates chromatin remodeling necessary for endocrine lineage commitment and terminal maturation. Our findings highlight a previously underappreciated role for ISL1 in preserving endocrine cell fate and function and offer insight into how its dysregulation may contribute to diabetes.

ISL1 is a known maturity-onset diabetes of the young candidate and type 2 diabetes susceptibility gene, yet its molecular role in pancreatic endocrine maturation has remained unresolved. Deletion of Isl1 in endocrine progenitors results in islets composed of dysfunctional α-cells lacking glucagon production and immature β-cells with impaired basal insulin secretion, ultimately accelerating diabetes progression. ISL1 functions as a transcriptional repressor guiding chromatin remodeling and transcriptional transitions toward hormone-producing endocrine cells. The metabolic phenotype resulting from Isl1 deletion is associated with sustained progenitor-like states and activation of diabetes- and stress-associated pathways, with distinct sex-specific responses observed between male and female mice.