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 Daniela Höffler; Victor Kreiner; Reagan Ching; Tess Tsai-Hsiu Lu; Ayush Semwal; Ben Johnson; Parijat Senapati; Adelheid Lempradl; Dustin Schones; Axel Imhof; Hui Shen; John Andrew Pospisilik

doi:10.1016/j.cmet.2023.03.008

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 Daniela Höffler
, Victor Kreiner
, Reagan Ching
, Tess Tsai-Hsiu Lu
, Ayush Semwal
, Ben Johnson
, Parijat Senapati
, Adelheid Lempradl
, Dustin Schones
, Axel Imhof
, Hui Shen
, John Andrew Pospisilik^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

36 Scopus citations

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.

Original language	English
Pages (from-to)	821-836.e7
Journal	Cell Metabolism
Volume	35
Issue number	5
DOIs	https://doi.org/10.1016/j.cmet.2023.03.008
State	Published - 2 May 2023
Externally published	Yes

Bibliographical note

Publisher Copyright:
© 2023 The Author(s)

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

H3K27me3
beta cells
bivalent genes
cell heterogeneity
chromatin organization
epigenetics
insulin
pancreatic islet
single cell

Access to Document

10.1016/j.cmet.2023.03.008

Cite this

Dror, E., Fagnocchi, L., Wegert, V., Apostle, S., Grimaldi, B., Gruber, T., Panzeri, I., Heyne, S., Höffler, K. D., Kreiner, V., Ching, R., Tsai-Hsiu Lu, T., Semwal, A., Johnson, B., Senapati, P., Lempradl, A., Schones, D., Imhof, A., Shen, H., & Pospisilik, J. A. (2023). Epigenetic dosage identifies two major and functionally distinct β cell subtypes. Cell Metabolism, 35(5), 821-836.e7. https://doi.org/10.1016/j.cmet.2023.03.008

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title = "Epigenetic dosage identifies two major and functionally distinct β cell subtypes",

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 (βHI and βLO). βHI cells exhibit ∼4-fold higher levels of H3K27me3, distinct chromatin organization and compaction, and a specific transcriptional pattern. βHI and βLO 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, βHI cells have increased mitochondrial mass, activity, and insulin secretion in vivo and ex vivo. Partial loss of function indicates that H3K27me3 dosage regulates βHI/βLO 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 βHI 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.",

keywords = "H3K27me3, beta cells, bivalent genes, cell heterogeneity, chromatin organization, epigenetics, insulin, pancreatic islet, single cell",

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note = "Publisher Copyright: {\textcopyright} 2023 The Author(s)",

year = "2023",

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doi = "10.1016/j.cmet.2023.03.008",

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Dror, E, Fagnocchi, L, Wegert, V, Apostle, S, Grimaldi, B, Gruber, T, Panzeri, I, Heyne, S, Höffler, KD, Kreiner, V, Ching, R, Tsai-Hsiu Lu, T, Semwal, A, Johnson, B, Senapati, P, Lempradl, A, Schones, D, Imhof, A, Shen, H & Pospisilik, JA 2023, 'Epigenetic dosage identifies two major and functionally distinct β cell subtypes', Cell Metabolism, vol. 35, no. 5, pp. 821-836.e7. https://doi.org/10.1016/j.cmet.2023.03.008

TY - JOUR

T1 - Epigenetic dosage identifies two major and functionally distinct β cell subtypes

AU - Dror, Erez

AU - Fagnocchi, Luca

AU - Wegert, Vanessa

AU - Apostle, Stefanos

AU - Grimaldi, Brooke

AU - Gruber, Tim

AU - Panzeri, Ilaria

AU - Heyne, Steffen

AU - Höffler, Kira Daniela

AU - Kreiner, Victor

AU - Ching, Reagan

AU - Tsai-Hsiu Lu, Tess

AU - Semwal, Ayush

AU - Johnson, Ben

AU - Senapati, Parijat

AU - Lempradl, Adelheid

AU - Schones, Dustin

AU - Imhof, Axel

AU - Shen, Hui

AU - Pospisilik, John Andrew

PY - 2023/5/2

Y1 - 2023/5/2

N2 - 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 (βHI and βLO). βHI cells exhibit ∼4-fold higher levels of H3K27me3, distinct chromatin organization and compaction, and a specific transcriptional pattern. βHI and βLO 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, βHI cells have increased mitochondrial mass, activity, and insulin secretion in vivo and ex vivo. Partial loss of function indicates that H3K27me3 dosage regulates βHI/βLO 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 βHI 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.

AB - 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 (βHI and βLO). βHI cells exhibit ∼4-fold higher levels of H3K27me3, distinct chromatin organization and compaction, and a specific transcriptional pattern. βHI and βLO 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, βHI cells have increased mitochondrial mass, activity, and insulin secretion in vivo and ex vivo. Partial loss of function indicates that H3K27me3 dosage regulates βHI/βLO 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 βHI 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.

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KW - beta cells

KW - bivalent genes

KW - cell heterogeneity

KW - chromatin organization

KW - epigenetics

KW - insulin

KW - pancreatic islet

KW - single cell

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U2 - 10.1016/j.cmet.2023.03.008

DO - 10.1016/j.cmet.2023.03.008

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C2 - 36948185

AN - SCOPUS:85153597359

SN - 1550-4131

VL - 35

SP - 821-836.e7

JO - Cell Metabolism

JF - Cell Metabolism

IS - 5

ER -

Epigenetic dosage identifies two major and functionally distinct β cell subtypes

Abstract

Bibliographical note

UN SDGs

Keywords

Access to Document

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