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 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.

The dynamic broad epigenetic (H3K4me3, H3K27ac) domain as a mark of essential genes

“…5 ). Transcription factors also recruit chromatin modifying enzymes [protein arginine methyltransferase 1 (PRMT1), CBP/300] to enhancers/super-enhancers and promoters [ 51 , 60 , 103 – 105 ]. PRMT1 is required to establish the active chromatin state and is needed for hematopoietic differentiation in avian and mammalian cells [ 103 , 105 , 106 ].…”

“…Thus, PRMT1 may have a role in activation of enhancers via the enzyme’s recruitment of CBP/p300 and H3K27 acetylation and in interaction of the enhancer/super-enhancer/locus control region with the target promoter, a step that can take place before enhancer activation [ 105 ]. Recently, it was reported that PRMT1 regulates the gene expression program in mouse mature β-cell and is required for maintaining mature β-cell identity [ 51 ]. These observations suggest that PRMT1 plays a pivotal role in the establishment of the broad epigenetic domain interactome.…”

Epigenetic modifications in pancreas development, diabetes, and therapeutics

“…Although nine PRMTs have been identified, PRMT1 catalyzes one‐third of the total arginine methylations in histone and nonhistone proteins 42 . The genetic ablation of Prmt1 in mice resulted in the loss of H4R3me2 and impairment of β‐cell function because of the restricted accessibility of key β‐cell transcription factors such as Nkx6.1, Mafa, Pdx1, and Neurod1 43 . PRMT5 is known to control β‐cell proliferation in association with menin, a scaffold protein.…”

Pancreatic β-cell specific loss ofE2f1impairs insulin secretion and β-cell identity through the epigenetic repression of non β-cell programs

“…Chromatin regulators and epigenomic features play important roles in the control of β -cell identity and plasticity (Arda et al, 2016;Avrahami et al, 2015;Campbell & Hoffman, 2016). Indeed, the modulation of islet enriched transcription factor activity, including Pdx1 or Nkx2.2, involves their interaction with coregulators such as Dnmt1, Dmnt3a or Hdac1 (Dhawan et al, 2011;Papizan et al, 2011;Spaeth et al, 2016) or their accessibility to chromatin, as demonstrated for the β -cell specific deletion of protein arginine methyltransferase 1 (Prmt1) that results in the loss of β -cell identity and diabetes development (Kim et al, 2020). In addition, recent studies also indicate that loss of Polycomb silencing in human and mouse β -cells contributes to loss of β -cell identity in diabetes (Lu et al, 2018).…”