Dror E.et al.
The mechanisms that specify and stabilize cell subtypes remain poorly understood. Here, we identify two major subtypes of pancreatic Î² cells based on histone mark heterogeneity (beta HI and beta LO). Beta HI cells exhibit 4-fold higher levels of H3K27me3, distinct chromatin organization and compaction, and a specific transcriptional pattern. Beta HI and beta LO 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, Î² cells have increased mitochondrial mass, activity, and insulin secretion in vivo and ex vivo. Partial loss of function indicates that H3K27me3 dosage regulates beta HI/beta LO ratio in vivo, suggesting that control of beta HI cell subtype identity and ratio is at least partially uncoupled. Both subtypes are conserved in humans, with beta HI cells enriched in humans with type 2 diabetes. Thus, epigenetic dosage is a novel regulator of cell subtype specification and identifies two functionally distinct beta cell subtypes.