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

28 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)

Keywords

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

UN SDGs

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

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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",

author = "Erez Dror and Luca Fagnocchi and Vanessa Wegert and Stefanos Apostle and Brooke Grimaldi and Tim Gruber and Ilaria Panzeri and Steffen Heyne and H{\"o}ffler, \{Kira Daniela\} and Victor Kreiner and Reagan Ching and \{Tsai-Hsiu Lu\}, Tess and Ayush Semwal and Ben Johnson and Parijat Senapati and Adelheid Lempradl and Dustin Schones and Axel Imhof and Hui Shen and Pospisilik, \{John Andrew\}",

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

year = "2023",

month = may,

day = "2",

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

UR - https://www.scopus.com/pages/publications/85153597359

U2 - 10.1016/j.cmet.2023.03.008

DO - 10.1016/j.cmet.2023.03.008

M3 - ???researchoutput.researchoutputtypes.contributiontojournal.article???

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

Keywords

UN SDGs

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