Loss of functional β-cell mass is an essential feature of type 2 diabetes, and maintaining mature β-cell identity is important for preserving a functional β-cell mass. However, it is unclear how β-cells achieve and maintain their mature identity. Here we demonstrate a novel function of protein arginine methyltransferase 1 (PRMT1) in maintaining mature β-cell identity. Prmt1 knockout in fetal and adult β-cells induced diabetes, which was aggravated by high-fat diet–induced metabolic stress. Deletion of Prmt1 in adult β-cells resulted in the immediate loss of histone H4 arginine 3 asymmetric dimethylation (H4R3me2a) and the subsequent loss of β-cell identity. The expression levels of genes involved in mature β-cell function and identity were robustly downregulated as soon as Prmt1 deletion was induced in adult β-cells. Chromatin immunoprecipitation sequencing and assay for transposase-accessible chromatin sequencing analyses revealed that PRMT1-dependent H4R3me2a increases chromatin accessibility at the binding sites for CCCTC-binding factor (CTCF) and β-cell transcription factors. In addition, PRMT1-dependent open chromatin regions may show an association with the risk of diabetes in humans. Together, our results indicate that PRMT1 plays an essential role in maintaining β-cell identity by regulating chromatin accessibility.

中文翻译：

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PRMT1 是维持成熟 β 细胞身份所必需的

功能性 β 细胞团的丧失是 2 型糖尿病的一个基本特征，维持成熟的 β 细胞特性对于保留功能性 β 细胞团很重要。然而，目前尚不清楚 β 细胞如何实现并保持其成熟特性。在这里，我们展示了蛋白质精氨酸甲基转移酶 1 (PRMT1) 在维持成熟 β 细胞身份方面的新功能。敲除胎儿和成人 β 细胞中的 Prmt1 会导致糖尿病，而高脂饮食引起的代谢压力会加剧这种情况。成人 β 细胞中 Prmt1 的缺失导致组蛋白 H4 精氨酸 3 不对称二甲基化 (H4R3me2a) 立即丧失，随后 β 细胞特性丧失。一旦在成人 β 细胞中诱导 Prmt1 缺失，参与成熟 β 细胞功能和身份的基因的表达水平就会强烈下调。染色质免疫沉淀测序和转座酶可及染色质测序分析表明，依赖 PRMT1 的 H4R3me2a 增加了 CCCTC 结合因子 (CTCF) 和 β 细胞转录因子结合位点的染色质可及性。此外，依赖 PRMT1 的开放染色质区域可能与人类患糖尿病的风险有关。总之，我们的结果表明 PRMT1 通过调节染色质的可及性，在维持 β 细胞特性方面发挥着重要作用。PRMT1 依赖性开放染色质区域可能与人类患糖尿病的风险有关。总之，我们的结果表明 PRMT1 通过调节染色质的可及性，在维持 β 细胞特性方面发挥着重要作用。PRMT1 依赖性开放染色质区域可能与人类患糖尿病的风险有关。总之，我们的结果表明 PRMT1 通过调节染色质的可及性，在维持 β 细胞特性方面发挥着重要作用。