Epigenetic dosage identifies two major and functionally distinct j3 cell subtypes

The mechanisms that specify and stabilize cell subtypes remain poorly understood. Here, we identify two ma-jor subtypes of pancreatic j3 cells based on histone mark heterogeneity (j3HI and j3LO). j3HI cells exhibit -4-fold higher levels of H3K27me3, distinct chromatin organization and compaction, and a specific transcriptional pattern. j3HI and j3LO cells also differ in size, morphology, cytosolic and nuclear ultrastructure, epigenomes, cell surface marker expression, and function, and can be FACS separated into CD24+ and CD24- fractions. Functionally, j3HI cells have increased mitochondrial mass, activity, and insulin secretion in vivo and ex vivo. Partial loss of function indicates that H3K27me3 dosage regulates j3HI/j3LO ratio in vivo, suggesting that con-trol of j3 cell subtype identity and ratio is at least partially uncoupled. Both subtypes are conserved in humans, with j3HI cells enriched in humans with type 2 diabetes. Thus, epigenetic dosage is a novel regulator of cell subtype specification and identifies two functionally distinct j3 cell subtypes.