FoxM1 coordinates cell division, protein synthesis, and mitochondrial activity in a subset of β cells during acute metabolic stress.

Autor:	Kobiita A; Institute of Molecular Health Sciences, ETH Zürich, Otto-Stern-Weg 7, 8093 Zürich, Switzerland., Silva PN; Institute of Molecular Health Sciences, ETH Zürich, Otto-Stern-Weg 7, 8093 Zürich, Switzerland., Schmid MW; MWSchmid GmbH, Hauptstrasse 34, 8750 Glarus, Switzerland., Stoffel M; Institute of Molecular Health Sciences, ETH Zürich, Otto-Stern-Weg 7, 8093 Zürich, Switzerland; Medical Faculty, Universitäts-Spital Zürich, Rämistrasse 100, 8091 Zürich, Switzerland. Electronic address: stoffel@biol.ethz.ch.
Jazyk:	angličtina
Zdroj:	Cell reports [Cell Rep] 2023 Aug 29; Vol. 42 (8), pp. 112986. Date of Electronic Publication: 2023 Aug 16.
DOI:	10.1016/j.celrep.2023.112986
Abstrakt:	Pancreatic β cells display functional and transcriptional heterogeneity in health and disease. The sequence of events leading to β cell heterogeneity during metabolic stress is poorly understood. Here, we characterize β cell responses to early metabolic stress in vivo by employing RNA sequencing (RNA-seq), assay for transposase-accessible chromatin with sequencing (ATAC-seq), single-cell RNA-seq (scRNA-seq), chromatin immunoprecipitation sequencing (ChIP-seq), and real-time imaging to decipher temporal events of chromatin remodeling and gene expression regulating the unfolded protein response (UPR), protein synthesis, mitochondrial function, and cell-cycle progression. We demonstrate that a subpopulation of β cells with active UPR, decreased protein synthesis, and insulin secretary capacities is more susceptible to proliferation after insulin depletion. Alleviation of endoplasmic reticulum (ER) stress precedes the progression of the cell cycle and mitosis and ensures appropriate insulin synthesis. Furthermore, metabolic stress rapidly activates key transcription factors including FoxM1, which impacts on proliferative and quiescent β cells by regulating protein synthesis, ER stress, and mitochondrial activity via direct repression of mitochondrial-encoded genes. Competing Interests: Declaration of interests The authors declare no competing interests. (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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