Institute of Molecular Health Sciences, ETH Zürich, Otto-Stern-Weg 7, 8093 Zürich, Switzerland.
MWSchmid GmbH, Hauptstrasse 34, 8750 Glarus, Switzerland.
Cell Rep. 2023 Aug 29;42(8):112986. doi: 10.1016/j.celrep.2023.112986. Epub 2023 Aug 16.
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.
胰岛β细胞在健康和疾病状态下表现出功能和转录组的异质性。然而，代谢应激导致β细胞异质性的发生过程目前仍知之甚少。在这里，我们通过 RNA 测序（RNA-seq）、转座酶可及染色质测序（ATAC-seq）、单细胞 RNA 测序（scRNA-seq）、染色质免疫沉淀测序（ChIP-seq）和实时成像，来描绘染色质重塑和基因表达调控未折叠蛋白反应（UPR）、蛋白质合成、线粒体功能和细胞周期进程的时空事件，以此来研究β细胞对早期代谢应激的反应，从而在体内对其进行了表征。我们证明了，在胰岛素耗竭后，具有活跃的 UPR、降低的蛋白质合成和胰岛素分泌能力的β细胞亚群更容易增殖。内质网（ER）应激的减轻先于细胞周期和有丝分裂的进展，并确保适当的胰岛素合成。此外，代谢应激会迅速激活关键转录因子，包括 FoxM1，它通过直接抑制线粒体编码基因，调节蛋白质合成、ER 应激和线粒体活性，对增殖和静止的β细胞产生影响。
