Aberrant DNA Methylation Involved in Obese Women with Systemic Insulin Resistance

Abstract

Background: Epigenetics has been recognized as a significant regulator in many diseases. White adipose tissue (WAT) epigenetic dysregulation is associated with systemic insulin resistance (IR). The aim of this study was to survey the differential methylation of genes in obese women with systemic insulin resistance by DNA methylation microarray.

Methods: The genome-wide methylation profile of systemic insulin resistant obese women was obtained from Gene Expression Omnibus database. After data preprocessing, differing methylation patterns between insulin resistant and sensitive obese women were identified by Student's t-test and methylation value differences. Network analysis was then performed to reveal co-regulated genes of differentially methylated genes. Functional analysis was also implemented to reveal the underlying biological processes related to systemic insulin resistance in obese women.

Results: Relative to insulin sensitive obese women, we initially screened 10,874 differentially methylated CpGs, including 7402 hyper-methylated sites and 6073 hypo-methylated CpGs. Our analysis identified 4 significantly differentially methylated genes, including SMYD3, UST, BCL11A, and BAI3. Network and functional analyses found that these differentially methylated genes were mainly involved in chondroitin and dermatan sulfate biosynthetic processes.

Conclusion: Based on our study, we propose several epigenetic biomarkers that may be related to obesity-associated insulin resistance. Our results provide new insights into the epigenetic regulation of disease etiology and also identify novel targets for insulin resistance treatment in obese women.

Keywords: DNA methylation; bioinformatics; insulin resistance; obesity.

Figure 1

Volcano plot exhibits the distribution of differential methylation CpG sites in obese women with insulin resistance. The abscissa indicates the mean methylation differences between insulin resistant and insulin sensitive obese women, and the ordinate shows the log transformed p value. Only 4 CpG sites were considered to be significantly differentially methylated (blue). True, indicates the genes that are significantly up-regulated; False, indicates the genes that are significantly down-regulated.

Figure 2

Hierarchical clustering illustrates DNA methylation patterns of the four differentially methylated genes in insulin resistant and insulin sensitive obese women. Each row is an individual CpG site and each column is a different sample. Color gradation from green to red denotes low to high DNA methylation, with color key ranging from 0 (no methylation; green) to 1 (complete methylation; red). The mean percent methylation value for each probe (red–blue scale) is the mean methylation value, after adjustment for covariates, for all samples.

Figure 3

The protein-protein sub-networks of four differentially methylated genes and their co-regulated genes.