Identification of two β-cell subtypes by 7 independent criteria

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.

doi:10.1101/2023.01.31.526222

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bioRxiv · 10.1101/2023.01.31.526222

Identification of two β-cell subtypes by 7 independent criteria

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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. HighlightsO_LIQuantitative H3K27me3 heterogeneity reveals 2 common {beta}-cell subtypes C_LIO_LI{beta}HI and {beta}LO cells are stably distinct by 7 independent sets of parameters C_LIO_LIH3K27me3 dosage controls {beta}HI / {beta}LO ratio in vivo C_LIO_LI{beta}HI and {beta}LO cells are conserved in humans and enriched in Type-2 diabetes C_LI

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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.. 2023-02-01. Identification of two β-cell subtypes by 7 independent criteria. https://doi.org/10.1101/2023.01.31.526222

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