Essential Role of Protein Arginine Methyltransferase 1 in Pancreas Development by Regulating Protein Stability of Neurogenin 3

Abstract

BackgroundProtein arginine methyltransferase 1 (PRMT1) is a major enzyme responsible for the formation of methylarginine in mammalian cells. Recent studies have revealed that PRMT1 plays important roles in the development of various tissues. However, its role in pancreas development has not yet been elucidated.MethodsPancreatic progenitor cell-specific Prmt1 knock-out (Prmt1 PKO) mice were generated and characterized for their metabolic and histological phenotypes and their levels of Neurog3 gene expression and neurogenin 3 (NGN3) protein expression. Protein degradation assays were performed in mPAC cells.ResultsPrmt1 PKO mice showed growth retardation and a severely diabetic phenotype. The pancreatic size and β-cell mass were significantly reduced in Prmt1 PKO mice. Proliferation of progenitor cells during the secondary transition was decreased and endocrine cell differentiation was impaired. These defects in pancreas development could be attributed to the sustained expression of NGN3 in progenitor cells. Protein degradation assays in mPAC cells revealed that PRMT1 was required for the rapid degradation of NGN3.ConclusionPRMT1 critically contributes to pancreas development by destabilizing the NGN3 protein.

Proteome-Wide Alterations of Asymmetric Arginine Dimethylation Associated With Pancreatic Ductal Adenocarcinoma Pathogenesis

“…In contrast to its high expression in breast cancer ( Wang et al, 2014 ), the greatly repressed expression of PRMT4 in PDAC cells also suggested that the pathogenic roles of PRMT4 in pancreatic cancer might be mediated by tissue-specific signaling mechanisms. In addition, other type I PRMTs such as PRMT1 also critically regulate pancreas development and PDAC pathogenesis ( Wang Y. et al, 2016 ; Lin et al, 2018 ; Lee et al, 2019 ; Song et al, 2020 ), and their pathogenic roles in PDAC cells deserve further investigations.…”

Arginine 65 methylation of Neurogenin 3 by PRMT1 is a prerequisite for development of hESCs into pancreatic endocrine cells

“…We confirmed the short half-life of NGN3 in both H1 and P- iKO hESCs during in vitro pancreatic endocrine differentiation, observing robust expression in the EP stage that fell abruptly by the EC stage (Figure S2C). Another previous study showed accumulation of NGN3 in the pancreas of P-KO mice from E14.5 to the postnatal stage (Lee et al, 2019). To determine whether P-KO is also associated with NGN3 accumulation in this study, we treated P-iKO cells with dox in the PE stage for 3 d and further differentiated them into EP cells (Figure 3A).…”

“…The role of PRMT1-mediated arginine methylation in pancreas development, however, is poorly understood. PRMT1-KO (PKO) mouse embryos exhibit prolonged NGN3 expression accompanied by reduced pancreatic β-cell mass and pancreatic hypoplasia after birth (Lee et al, 2019). This suggests PRMT1 may control NGN3 stability in mammalian pancreatic development.…”

“…PRMT1-mediated arginine methylation plays an important role in the stability and localization of non-histone proteins, such as FOXO1, TSC2, and progesterone receptor (Gen et al, 2020; Malbeteau et al, 2020; Yamagata et al, 2008). Recently, Prmt1- knockout (PKO) mouse embryos showed slower degradation of NGN3 from E14.5, leading to severe postnatal pancreatic hypoplasia (Lee et al, 2019). This suggests PRMT1 is associated with NGN3 stability in pancreatic development.…”

Protein Arginine Methyltransferase 1 Is Essential for the Meiosis of Male Germ Cells

“…Although PRMT1 whole-body KO mice are embryonically lethal [ 22 ], conditional KO studies have revealed the important roles of PRMT1 in different cellular processes. For example, the deletion of PRMT1 from the muscular system and neural progenitors leads to the failure of muscle differentiation and brain demyelination, respectively [ 23 , 24 ]. PRMT1 has been considered a key factor in the epigenetic control and maintenance of the expression levels of genes involved in the determination of the functions and identities of mature β-cells [ 25 ].…”