Link to bioRxiv paper:
http://biorxiv.org/cgi/content/short/2023.01.31.526222v1?rss=1

Authors: Dror, E., Fagnocchi, L., Wegert, V., Apostle, S., Grimaldi, B., Gruber, T., Panzeri, I., Heyne, S., Hoeffler, K. D., Kreiner, V., Ching, R., Lu, T. T.-H., Semwal, A., Johnson, B., Senapati, P., Lempradl, A. M., Schones, D., Imhof, A., Shen, H., Pospisilik, J. A.

Abstract:
Despite the recent explosion in surveys of cell-type heterogeneity, the mechanisms that specify and stabilize highly related cell subtypes remain poorly understood. Here, focusing initially on exploring quantitative histone mark heterogeneity, we identify two major sub-types of pancreatic {beta}-cells ({beta}HI and {beta}LO). {beta}HI and {beta}LO cells differ in their size, morphology, cytosolic and nuclear ultrastructure, transcriptional output, epigenomes, cell surface marker, and function. Importantly, {beta}HI and {beta}LO cells can be FACS separated live into CD24+ ({beta}HI) and CD24- ({beta}LO) fractions. From an epigenetic viewpoint, {beta}HI-cells exhibit ~4-fold higher levels of H3K27me3, more compacted chromatin, and distinct chromatin organization that associates with a specific pattern of transcriptional output. Functionally, {beta}HI cells have increased mitochondrial mass, activity, and insulin secretion both in vivo and ex vivo. Critically, Eed and Jmjd3 loss-of-function studies demonstrate that H3K27me3 dosage is a significant regulator of {beta}HI / {beta}LO cell ratio in vivo, yielding some of the first-ever specific models of {beta}-cell sub-type distortion. {beta}HI and {beta}LO sub-types are conserved in humans with {beta}HI-cells enriched in human Type-2 diabetes. These data identify two novel and fundamentally distinct {beta}-cell subtypes and identify epigenetic dosage as a novel regulator of {beta}-cell subtype specification and heterogeneity.

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