PRMT4 is involved in insulin secretion via the methylation of histone H3 in pancreatic β cells

Abstract

The relationship between protein arginine methyltransferases (PRMTs) and insulin synthesis in b cells is not yet well understood. In the present study, we showed that PRMT4 expression was increased in INS-1 and HIT-T15 pancreatic b cells under high-glucose conditions. In addition, asymmetric dimethylation of Arg17 in histone H3 was significantly increased in both cell lines in the presence of glucose. The inhibition or knockdown of PRMT4 suppressed glucose-induced insulin gene expression in INS-1 cells by 81.6 and 79% respectively. Additionally, the overexpression of mutant PRMT4 also significantly repressed insulin gene expression. Consistently, insulin secretion induced in response to high levels of glucose was decreased by both PRMT4 inhibition and knockdown. Moreover, the inhibition of PRMT4 blocked high-glucose-induced insulin gene expression and insulin secretion in primary pancreatic islets. These results indicate that PRMT4 might be a key regulator of high-glucoseinduced insulin secretion from pancreatic b cells via H3R17 methylation.

Effects of unaltered and bioconverted mulberry leaf extracts on cellular glucose uptake and antidiabetic action in animals

“…AKRIN-011 T; Shivayagi, Gunma, Japan) according to the manufacturer’s instructions. The amount of insulin released from HIT-T15 cells into the media was measured as previously described [34]. HIT-T15 pancreatic β-cells seeded on a 24-well at a density of 2 × 10 5 cells/well were treated with RPMI-1640 medium supplemented with 10% FBS and 11.1 mM glucose and were cultured for 2 days.…”

“…Then the cell medium was replaced with DMEM containing 10% FBS, which was replaced every 2 days until day 8. HIT-T15 pancreatic β-cells were cultured at 37 °C in a 5% CO 2 atmosphere in RPMI-1640 culture medium containing 10% FBS, 0.8 mM glucose, 100 U/mL penicillin, and 100 μg/mL streptomycin, and were subcultured for 3–5 days [34].…”

Comparative transcriptome analysis identifies CARM1 and DNMT3A as genes associated with osteoporosis

“…The CARM1 gene codes for a histone-arginine methyltransferase functioning as both a coactivator and a methyltransferase 34 , which methylates both histones and non-histone substrates and which modulates gene expression by interacting with several transcription factors, and is overexpressed in different types of cancer 35 – 37 . Interestingly, CARM1 expression has been described as higher in GG homozygous individuals (SNP rs12460421) than in other genotypes ( 38 , and GTEx Portal, https://www.gtexportal.org ), and as involved in carbohydrate-induced insulin secretion via the methylation of arginine 17 of histone H3 in pancreatic b cells 32 . If this is the case, it is reasonable to assume that women with GG genotype for the SNP of the CARM1 gene could have experienced lifelong elevated plasma insulin levels after carbohydrate ingestion.…”

“…Given that the CARM1 gene has been associated with insulin secretion 32 , we conducted a multivariate regression study to detect if the CARM1 SNP was independently associated with insulin level if confounder variables such as anthropometric data, lipids or fasting glucose, were included in the model. As seen in Table 6 the CARM1 SNP association remained statistically significant after adjustment.…”

Targeting epigenetic mechanisms in diabetic wound healing

“…Compared to lysine modification, there is much less information regarding histone arginine methylation in diabetic complications, including wound healing. A few studies have shown that PRMTs are involved in insulin secretion in β-cells and some are overexpressed in diabetes (122)(123)(124). However, PRMTs can, not only methylate histones, but also non-histone proteins (121).…”