Identification of hub-methylated differentially expressed genes in patients with gestational diabetes mellitus by multi-omic WGCNA basing epigenome-wide and transcriptome-wide profiling

Abstract

Gestational diabetes mellitus (GDM), defined as dysglycaemia that is detected during pregnancy for the first time, has become a global health burden. GDM was found to be correlated to epigenetic changes, which would cause abnormal expression of placental genes. In the present study, we performed multi-omic weighted gene coexpression network analysis (WGCNA) to systematically identify the hub genes for GDM using both epigenome- and transcriptome-wide microarray data. Two microarray datasets (GSE70493 and GSE70494) were downloaded from the Gene Expression Omnibus (GEO) database. GEO2R was used to screen differentially expressed genes (DEGs) and differentially methylated genes (DMGs) between normal and GDM samples, separately. The results of WGCNA found that 15 modules were identified and the MEblack module had a significantly negative correlation with GDM (r = -.28, P = .03). GO enrichment analysis by BinGO of the MEblack module showed that genes were primarily enriched for the presentation of antigen processing, regulation of interferon-α production and interferon-γ-mediated signaling pathway. By comparing the DEGs, DMGs and hub genes in the coexpression network, we identified five hypermethylated, lowly expressed genes (ABLIM1, GRHL1, HLA-F, NDRG1, and SASH1) and one hypomethylated, highly expressed gene (EIF3F) as GDM-related hub DMGs. Moreover, the expression levels of ABLIM1, GRHL1, HLA-F, NDRG1, and SASH11 in the GDM patients and healthy controls were validated by a real-time quantitative polymerase chain reaction. Finally, gene set enrichment analysis showed that the biological function of cardiac muscle contraction was enriched for four GDM-related hub DMGs (ABLIM1, GRHL1, NDRG1, and SASH1). Analysis of this study revealed that dysmethylated hub genes in GDM placentas might affect the placental function and thus, take part in GDM pathogenesis and fetal cardiac development.

Keywords: WGCNA; epigenome; gestational diabetes mellitus; transcriptome.