Association between promoter DNA methylation and gene expression in the pathogenesis of ischemic stroke

Abstract

To assess DNA methylation sites as well as gene expression related to ischemic stroke (IS) and comprehensively reveal their correlation and possible pathological mechanisms, we implemented (1) genome-wide DNA methylation profiling from the GEO repository related to IS with and without symptoms; (2) identification of differentially methylation positions (DMPs) and genes (DMGs), functional enrichment analysis along with DMG regulatory network construction; (3) validation tests of 2 differential methylation positions of interest as well as analogous gene expression in other datasets and in IS patients and controls; and (4) correlation analysis of DNA methylation and mRNA expression data. In total, 870 DMPs were physically located within 693 DMGs. After disease ontology (DO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway, gene ontology (GO), protein-protein interaction (PPI) network construction as well as module analysis, HLA-DRB1 and HLA-DQB1 were identified. Their expression was validated in 4 other datasets but was significant in only 1, and the expression was lower in the IS group (P < 0.05). After validation in IS patients and controls, we found that these two genes showed more hypermethylation and lower expression levels in the IS group (P < 0.001). The methylation of genes was negatively associated with their expression (P < 0.05). The current study recognized a connection among DNA methylation and gene expression and emphasized the prominence of HLA-DRB1 and HLA-DQB1 in IS pathogenesis.

Pathogenesis of Ischemic Stroke: Role of Epigenetic Mechanisms

“…The role of promoter DNA methylation in the pathogenesis of IS has been well investigated in recent years (Table 1) [39,40]. In general, the global level of DNA methylation is higher in animal models of IS and is associated with higher activity of DNMT in the brain.…”

The Role of DNA Methylation in Ischemic Stroke: A Systematic Review

“…The characteristics of eligible studies were shown in Supplementary Table 2. Of the 20 studies, 17 were casecontrol studies (26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42), two were prospective cohort studies (43,44), and one was a cross-sectional study (45). Participants of the included studies were mostly older adults, with mean age ranging from 47.4 to 75.0 years.…”

“…Eighteen studies had an independent evaluation for the diagnosis of IS and claimed the use of imaging tests such as brain computed tomography, magnetic resonance imaging, or magnetic resonance diffusion weighted imaging (26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42)44). Nineteen out of 20 studies assessed DNA methylation from acute/subacute stroke patients (26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43)(44). Seventeen studies were assessed as high or medium-quality, and three studies were evaluated as low-quality (Supplementary Table 3 for casecontrol studies, Supplementary Table 4 for cohort studies and cross-sectional studies).…”

“…Among which, a maximum of 438 CpG sites were identified to be differentially methylated in IS cases compared to controls. Four studies conducted validation tests, and 26 candidate genes were detected to be associated with IS (27,37,39,40). However, one study observed no association between methylation and IS (45).…”

“…However, one study observed no association between methylation and IS (45). Three studies conducted enrichment analyses showing that the identified loci were related to several biological pathways including, inflammation, angiogenesis, metabolic, and immunerelated function (27,39,40).…”