PRMT1 Is Required for the Maintenance of Mature beta-Cell Identity

Abstract

Loss of functional beta-cell mass is an essential feature of type 2 diabetes, and maintaining mature beta-cell identity is important for preserving a functional beta-cell mass. However, it is unclear how beta-cells achieve and maintain their mature identity. Here we demonstrate a novel function of protein arginine methyltransferase 1 (PRMT1) in maintaining mature beta-cell identity. Prmt1 knockout in fetal and adult beta-cells induced diabetes, which was aggravated by high-fat diet-induced metabolic stress. Deletion of Prmt1 in adult beta-cells resulted in the immediate loss of histone H4 arginine 3 asymmetric dimethylation (H4R3me2a) and the subsequent loss of beta-cell identity. The expression levels of genes involved in mature beta-cell function and identity were robustly downregulated as soon as Prmt1 deletion was induced in adult beta-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 beta-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 beta-cell identity by regulating chromatin accessibility.