NT5C2 methylation regulatory interplay between DNMT1 and insulin receptor in type 2 diabetes

Abstract

Epigenetics alternation of non-genetic variation and genome-wide association study proven allelic variants may associate with insulin secretion in type 2 diabetes (T2D) development. We analyzed promoter DNA methylation array to evaluate the associated with increased susceptibility to T2D (30 cases, 10 controls) and found 1,091 gene hypermethylated in promoter regions. We performed the association study of T2D and found 698 single nucleotide polymorphisms in exon and promoter sites by using 2,270 subjects (560 cases, 1,710 controls). A comparison of DNA hypermethylation and gene silencing of mouse T2D results in our T2D patients’ results showed that the 5′-nucleotidase, cytosolic II (NT5C2) and fucosyltransferase 8 (FUT8) genes were strongly associated with increased susceptibility to T2D. DNA hypermethylation in promoter regions reduced NT5C2 gene expression, but not FUT8 in T2D patients. NT5C2 protein expression was decreased in pancreatic β-cells from T2D mice. Transient transfection NT5C2 into RIN-m5F cells down-regulated DNA methyltransferase I (DNMT1) expression and up-regulation of the insulin receptor. Moreover, NT5C2 knockdown induced in DNMT1 overexpression and insulin receptor inhibition. Taken together, these results showed that NT5C2 epigenetically regulated insulin receptor in patients and mice with T2D, and maybe provide for T2D therapy strategy.

ZNF354C Mediated by DNMT1 Ameliorates Lung Ischemia-Reperfusion Oxidative Stress Injury by Reducing TFPI Promoter Methylation to Upregulate TFPI

“…Vast evidence suggests that DNMT1 can regulate cell cycle and tumor suppressor gene expression, which is crucial in tumor metastasis and linked to poor prognosis [ 23 , 24 ]. Besides, studies have confirmed that DNMT1 is associated with other common diseases, such as type II diabetes [ 25 ], Alzheimer's disease [ 26 ], and periodontal disease [ 27 ]. Recent research also revealed that DNMT1 can mediate the polarization of M1 alveolar macrophages in ALI [ 28 ].…”

The Insulin Receptor: An Important Target for the Development of Novel Medicines and Pesticides

“…The pattern of DNA methylation in the genome is achieved by DNA methyltransferases such as DNMT1, DNMT3A, and DNMT3B [ 229 , 230 , 231 ]. DNMT1 affects IR gene expression through the transfection of 5′-nucleotidase, cytosolic II (NT5C2), an enzyme that dephosphorylates noncyclic nucleoside monophosphates into nucleoside and inorganic phosphate [ 232 , 233 ] ( Figure 5 ). DNMT1 epigenetically regulates NT5C2 and the IR.…”

“…DNMT1 epigenetically regulates NT5C2 and the IR. Overexpression of DNMT1 stimulated DNA hypermethylation of NT5C2, leading to the silencing of the NT5C2 gene and the inhibition of IR gene expression [ 32 , 232 ]. Knockdown of NT5C2 induced the overexpression of DNMT1 and inhibition of the IR [ 232 ].…”

“…Overexpression of DNMT1 stimulated DNA hypermethylation of NT5C2, leading to the silencing of the NT5C2 gene and the inhibition of IR gene expression [ 32 , 232 ]. Knockdown of NT5C2 induced the overexpression of DNMT1 and inhibition of the IR [ 232 ]. In contrast, overexpression of NT5C2 downregulated the expression of DNMT1 and upregulated the activation of the IR in RIN-m5F cells.…”

Exploring biomarkers and transcriptional factors in type 2 diabetes by comprehensive bioinformatics analysis on RNA-Seq and scRNA-Seq data

“…Of these, T2D is the most common type of diabetes, accounting for 90–95% of all diabetes cases, and is primarily characterized by pancreatic beta-cell dysfunction and insulin resistance ( 2 ). T2D can lead to serious clinical complications such as diabetic cardiomyopathy, retinopathy, nephropathy, and neuropathy, with high rates of disability and mortality ( 3 ). As lifestyle habits have changed, the number of T2D patients globally has increased significantly.…”