Zhang Xu, Shan Aijing, Chen Jie, Cao Yanan, Jiang Xiuli
Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, National Clinical Research Centre for Metabolic Diseases, State Key Laboratory of Medical Genomics, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission, Research Unit of Clinical and Basic Research on Metabolic Diseases of Chinese Academy of Medical Sciences, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
Ruijin Yangtze River Delta Health Institute, Wuxi Branch of Ruijin Hospital, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
Sci Rep. 2025 Mar 29;15(1):10835. doi: 10.1038/s41598-025-93799-4.
The modification of N6-methyladenosine (mA) influences the translation and stability of transcripts, allowing for the coordination of gene regulation during cell state maintenance and transition. Deregulation of components in the mA regulatory network is associated with glucose homeostasis and development of diabetes. In this study, we investigated the functional role of Mettl3, which is the key component of the mA methyltransferase complex, in regulating β-cell identity and function in two pancreatic β-cell-specific Mettl3 knockout mouse models. The glucose metabolic phenotype, β-cell proliferation, islet architecture and insulin secretion were analyzed in vivo. We next analyzed the expression levels of genes associated with endoplasmic reticulum (ER) stress in the Mettl3 ablated islets. MeRIP-qPCR was applied to detect the mA modification enrichment of Ire1α mRNA. Adenovirus-mediated Mettl3 infection was performed on islets to explore the effect of Mettl3 overexpression on ER stress and insulin secretion. Our results showed that Mettl3 deficiency led to loss of β-cell identity and impaired insulin secretion in mice. Depletion of Mettl3 verified the mA modification in Ire1α and consequently induced ER stress in islet cells. Mettl3 overexpression in islets could alleviate ER stress and improve the insulin secretion capacity. Our findings demonstrated that Mettl3 was an important regulator of ER stress and insulin secretion in mouse pancreatic β-cells.
N6-甲基腺苷（mA）的修饰会影响转录本的翻译和稳定性，从而在细胞状态维持和转变过程中实现基因调控的协调。mA调控网络中各组分的失调与葡萄糖稳态及糖尿病的发展有关。在本研究中，我们在两种胰腺β细胞特异性Mettl3基因敲除小鼠模型中，研究了mA甲基转移酶复合物的关键组分Mettl3在调节β细胞特性和功能中的作用。在体内分析了葡萄糖代谢表型、β细胞增殖、胰岛结构和胰岛素分泌。接下来，我们分析了Mettl3缺失的胰岛中与内质网（ER）应激相关基因的表达水平。应用MeRIP-qPCR检测Ire1α mRNA的mA修饰富集情况。对胰岛进行腺病毒介导的Mettl3感染，以探究Mettl3过表达对ER应激和胰岛素分泌的影响。我们的结果表明，Mettl3缺陷导致小鼠β细胞特性丧失和胰岛素分泌受损。Mettl3的缺失证实了Ire1α中的mA修饰，从而在胰岛细胞中诱导了ER应激。胰岛中Mettl3的过表达可减轻ER应激并提高胰岛素分泌能力。我们的研究结果表明，Mettl3是小鼠胰腺β细胞中ER应激和胰岛素分泌的重要调节因子。
