Epigenetic dosage identifies two major and functionally distinct β cell subtypes
Erez Dror, Luca Fagnocchi, Vanessa Wegert, Stefanos Apostle, Brooke Grimaldi, Tim Gruber, Ilaria Panzeri, Steffen Heyne, Kira D. Höffler, Victor Kreiner, Reagan W. Ching, Tess Tsai-Hsiu Lu, Ayush Semwal, Ben K. Johnson, Parijat Senapati, Adelheid Lempradl, Dustin E. Schones, Axel Imhof, Hui Shen, J. Andrew Pospisilik
Abstract
The mechanisms that specify and stabilize cell subtypes remain poorly understood. Here, we identify two major subtypes of pancreatic β cells based on histone mark heterogeneity (β HI and β LO ). β HI cells exhibit ∼4-fold higher levels of H3K27me3, distinct chromatin organization and compaction, and a specific transcriptional pattern. β HI and β 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, β HI cells have increased mitochondrial mass, activity, and insulin secretion in vivo and ex vivo . Partial loss of function indicates that H3K27me3 dosage regulates β HI /β LO ratio in vivo , suggesting that control of β cell subtype identity and ratio is at least partially uncoupled . Both subtypes are conserved in humans, with β 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 β cell subtypes.