PRMT1 is Required for the Maintenance of Mature β Cell Identity

Abstract

Loss of functional β cell mass is an essential feature of type 2 diabetes, and maintaining mature 60  cell identity is important for preserving a functional β cell mass. However, it is unclear how β cells 61 achieve and maintain their mature identity. Here, we demonstrate a novel function of PRMT1 in 62 maintaining mature β cell identity. Prmt1 knockout in fetal and adult β cells induced diabetes, which 63 was aggravated by high fat diet-induced metabolic stress. Deletion of Prmt1 in adult β cells resulted 64 in the immediate loss of histone H4 arginine 3 asymmetric di-methylation (H4R3me2a) and the 65 subsequent loss of β cell identity. The expression levels of genes involved in mature β cell function 66 and identity were robustly downregulated as soon as Prmt1 deletion was induced in adult β cells. ChIP67 seq and ATAC-seq analyses revealed that PRMT1-dependent H4R3me2a increases chromatin 68 accessibility at the binding sites for CTCF and β cell transcription factors. In addition, PRMT1-69 dependent open chromatin regions may show an association with the risk of diabetes in humans. 70 Together, our results indicate that PRMT1 plays an essential role in maintaining β cell identity by 71 regulating chromatin accessibility.