Detection of type 2 diabetes related modules and genes based on epigenetic networks

Abstract

BackgroundType 2 diabetes (T2D) is one of the most common chronic metabolic diseases characterized by insulin resistance and the decrease of insulin secretion. Genetic variation can only explain part of the heritability of T2D, so there need new methods to detect the susceptibility genes of the disease. Epigenetics could establish the interface between the environmental factor and the T2D Pathological mechanism.ResultsBased on the network theory and by combining epigenetic characteristics with human interactome, the weighted human DNA methylation network (WMPN) was constructed, and a T2D-related subnetwork (TMSN) was obtained through T2D-related differentially methylated genes. It is found that TMSN had a T2D specific network structure that non-fatal metabolic disease causing genes were often located in the topological and functional periphery of network. Combined with chromatin modifications, the weighted chromatin modification network (WCPN) was built, and a T2D-related chromatin modification pattern subnetwork was obtained by the TMSN gene set. TCSN had a densely connected network community, indicating that TMSN and TCSN could represent a collection of T2D-related epigenetic dysregulated sub-pathways. Using the cumulative hypergeometric test, 24 interplay modules of DNA methylation and chromatin modifications were identified. By the analysis of gene expression in human T2D islet tissue, it is found that there existed genes with the variant expression level caused by the aberrant DNA methylation and (or) chromatin modifications, which might affect and promote the development of T2D.ConclusionsHere we have detected the potential interplay modules of DNA methylation and chromatin modifications for T2D. The study of T2D epigenetic networks provides a new way for understanding the pathogenic mechanism of T2D caused by epigenetic disorders.

Clinical relevance of epigenetics in the onset and management of type 2 diabetes mellitus

“…74 Another study analyzed the epigenetic bases of T2DM by means of network-based approaches relating DNA methylation, chromatin modifications, and gene expression with T2DM. 75 As result, it has been demonstrated that the variance in gene expression observed in human islet tissue from T2DM patients was due to specific epigenetic modifications. 75 Besides, T2DM has been associated to the expression of specific mRNAs and miRNAs by applying several bioinformatics tools, such as functional enrichment analysis, gene set enrichment analysis, gene set analysis, and the VENNY software to microarray data.…”

“…75 As result, it has been demonstrated that the variance in gene expression observed in human islet tissue from T2DM patients was due to specific epigenetic modifications. 75 Besides, T2DM has been associated to the expression of specific mRNAs and miRNAs by applying several bioinformatics tools, such as functional enrichment analysis, gene set enrichment analysis, gene set analysis, and the VENNY software to microarray data. 76 Recently, an interesting bioinformatics procedure allowed the identification of SNPs in miRNA binding sites associated with T2DM.…”

Perturbation of interactome through micro-RNA and methylome analysis in diabetes endophenotypes: the PIRAMIDE pathogenic clinical study design

“…The weighted human DNA methylation PPI network (WMPN) will be construct to obtain a T2D-related subnetwork based on differentially methylated genes both in CD4+ and CD8+ T cells isolated from cases and controls. 28 The TargetScan algorithm, by searching the conserved seed pairing regions in the 3' untraslated regions (UTR) of genes based on whole genome alignment, will be used to robustly predict miRNA-target gene pairs both in CD4+ and CD8+ T cells isolated from cases and controls. 31…”

“…[24][25][26] The application of network-based tools has largely contributed to improve our knowledge regarding both genetic and epigenetic mechanisms underlying T2D-related endophenotypes and its macrovascular complications. [27][28][29] The perturbation of interactome through microRNA and methylome analysis in diabetes endophenotypes: the PIRAMIDE pathogenic clinical study design (NCT03792607) is a cross-sectional clinical research network-based approach aimed to identify putative interactions between DNA methylation and microRNAs (miRNAs) associated with T2D-related candidate genes ( Figure 1). The second endpoint will be to evaluate the predictive value of these putative epigenetic interactions regarding the insurgence of macrovascular complications in T2D patients respect with controls.…”

Long Non-coding RNAs: key players in brain and central nervous system development

“…Based on current view of points and accumulating evidences, epigenetic factors are considered to affect mammalian development and cell differentiation. Furthermore, aberrant epigenetic modification changes by DNA methylation and histone modifications have key roles in human diseases (Kaut et al, 2014;Coppieters et al, 2013;Besingi and Johansson, 2014;Zykovich et al, 2013;Bryant et al, 2014;Sanchez-Mut et al, 2013;Robertson, 2005;MacDonald and Roskams, 2009;Liu et al, 2014;Lv et al, 2010;Lv et al, 2012;Liu et al, 2011;. For example, the enzymes and complexes such as Polycomb proteins and Trithorax-group proteins, are basal for developmental processes (Kouzarides, 2007;Ringrose and Paro, 2007).…”