Epigenetic dosage identifies two major and functionally distinct β cell subtypes

Dror, Erez; Fagnocchi, Luca; Wegert, Vanessa; Apostle, Stefanos; Grimaldi, Brooke; Gruber, Tim; Panzeri, Ilaria; Heyne, Steffen; Höffler, Kira Daniela; Kreiner, Victor; Ching, Reagan; Lu, Tess Tsai-Hsiu; Semwal, Ayush; Johnson, Ben; Senapati, Parijat; Lempradl, Adelheid; Schones, Dustin; Imhof, Axel; Shen, Hui; Pospisilik, John Andrew

doi:10.1016/j.cmet.2023.03.008

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Epigenetic dosage identifies two major and functionally distinct β cell subtypes

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Dror, Erez
Department of Epigenetics, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Wegert, Vanessa
Department of Epigenetics, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Panzeri, Ilaria
Department of Epigenetics, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Heyne, Steffen
Department of Epigenetics, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Höffler, Kira Daniela
Department of Epigenetics, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Kreiner, Victor
Department of Epigenetics, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Ching, Reagan
Department of Epigenetics, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Lu, Tess Tsai-Hsiu
Department of Epigenetics, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Lempradl, Adelheid
Department of Epigenetics, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

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Pospisilik, John Andrew
Department of Epigenetics, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

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https://www.sciencedirect.com/science/article/pii/S1550413123000864?via%3Dihub
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Citation

Dror, E., Fagnocchi, L., Wegert, V., Apostle, S., Grimaldi, B., Gruber, T., et al. (2023). Epigenetic dosage identifies two major and functionally distinct β cell subtypes. Cell Metabolism, 35, 821-836. doi:10.1016/j.cmet.2023.03.008.

Cite as: https://hdl.handle.net/21.11116/0000-000D-1026-6

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.