Differential DNA methylation of MSI2 and its correlation with diabetic traits

Abstract

Differential DNA methylation with hyperglycemia is significantly associated with Type 2 Diabetes (T2D). Longtime extended exposure to high blood glucose levels can affect the epigenetic signatures in all organs. However, the relevance of the differential DNA methylation changes with hyperglycemia in blood with pancreatic islets remains unclear. We investigated differential DNA methylation in relation to glucose homeostasis based on the Oral Glucose Tolerance Test (OGTT) in a population-based cohort. We found a total of 382 differential methylation sites from blood DNA in hyperglycemia and type 2 diabetes subgroups using a longitudinal and cross-sectional approach. Among them, three CpG sites were overlapped; they were mapped to the MSI2 and CXXC4 genes. In a DNA methylation replication study done by pyrosequencing (n = 440), the CpG site of MSI2 were shown to have strong associations with the T2D group (p value = 2.20E-16). The differential methylation of MSI2 at chr17:55484635 was associated with diabetes-related traits, in particular with insulin sensitivity (QUICKI, p value = 2.20E-16) and resistance (HOMA-IR, p value = 1.177E-07). In human pancreatic islets, at the single-base resolution (using whole-genome bisulfite sequencing), the 292 CpG sites in the ±5kb at chr17:55484635 were found to be significantly hypo-methylated in donors with T2D (average decrease = 13.91%, 95% confidence interval (CI) = 4.18~ 17.06) as compared to controls, and methylation patterns differed by sex (-9.57%, CI = -16.76~ -6.89) and age (0.12%, CI = -11.17~ 3.77). Differential methylation of the MSI2 gene (chr17:55484635) in blood and islet cells is strongly related to hyperglycemia. Our findings suggest that epigenetic perturbation on the target site of MSI2 gene in circulating blood and pancreatic islets should represent or affect hyperglycemia.

Blood-Based DNA Methylation Biomarkers for Type 2 Diabetes: Potential for Clinical Applications

“…More recently, Jeon et al (88) investigated genome-wide DNA methylation changes in peripheral blood related to hypoglycaemia in a longitudinal Korean population-based cohort (88). They identified hypomethylation of two genes, Musashi RNA-Binding Protein 2 ( MSI2 ) and CXXC-Type Zinc Finger Protein 4 ( CXXC4 ), in individuals with T2D and impaired glucose tolerance, compared to healthy controls.…”

DNA methylation in the pathogenesis of type 2 diabetes in humans

“…In addition to this, Jeon et al. presented WGBS data on a 10 kb stretch in the MSI2 gene showing methylation differences in islet preparations from two donors with T2D and 16 non-diabetic donors [21] . The functional relevance of this finding was not tested, however.…”

The role of DNA methylation in the pathogenesis of type 2 diabetes mellitus

“…A further analysis showed that MSI2 was significantly associated with T2DM, with the DNA methylation of this gene considerably decreased in the blood and pancreatic islets from the T2DM donors. In addition, increased MSI2 DNA methylation was positively correlated with increased insulin sensitivity ( QUICKI ) and decreased insulin resistance (HOMA-IR) [ 109 ].…”

“…However, no gene expression analysis was conducted in this study to confirm or deny this conclusion. The authors also suggested that the hypomethylation at chr17:55484635 may affect the expression of other genes [ 109 ].…”