Zhang Xiaokang, Xiang Yang, He Dingdong, Liang Bin, Wang Chen, Luo Jing, Zheng Fang
Department of Clinical Laboratory Medicine and Center for Gene Diagnosis, Zhongnan Hospital of Wuhan University, Wuhan, China.
Front Genet. 2020 Sep 9;11:778. doi: 10.3389/fgene.2020.00778. eCollection 2020.
DNA methylation plays an essential role in the pathogenesis of coronary artery disease (CAD) through regulating mRNA expressions. This study aimed to identify hub genes regulated by DNA methylation as biomarkers of CAD. Gene expression and methylation datasets of peripheral blood leukocytes (PBLs) of CAD were downloaded from the Gene Expression Omnibus (GEO) database. Subsequently, multiple computational approaches were performed to analyze the regulatory networks and to recognize hub genes. Finally, top hub genes were verified in a case-control study, based on their differential expressions and methylation levels between CAD cases and controls. In total, 535 differentially expressed-methylated genes (DEMGs) were identified and partitioned into 4 subgroups. TSS200 and 5'UTR were confirmed as high enrichment areas of differentially methylated CpGs sites (DMCs). The function of DEMGs is enriched in processes of histone H3-K27 methylation, regulation of post-transcription and DNA-directed RNA polymerase activity. Pathway enrichment showed DEMGs participated in the VEGF signaling pathway, adipocytokine signaling pathway, and PI3K-Akt signaling pathway. Besides, expressions of hub genes fibronectin 1 (FN1), phosphatase (PTEN), and tensin homolog and RNA polymerase III subunit A (POLR3A) were discordantly expressed between CAD patients and controls and related with DNA methylation levels. In conclusion, our study identified the potential biomarkers of PBLs for CAD, in which FN1, PTEN, and POLR3A were confirmed.
DNA甲基化通过调节mRNA表达在冠状动脉疾病（CAD）的发病机制中发挥重要作用。本研究旨在鉴定受DNA甲基化调控的关键基因作为CAD的生物标志物。从基因表达综合数据库（GEO）下载CAD患者外周血白细胞（PBLs）的基因表达和甲基化数据集。随后，采用多种计算方法分析调控网络并识别关键基因。最后，基于CAD病例与对照之间的差异表达和甲基化水平，在病例对照研究中对顶级关键基因进行验证。总共鉴定出535个差异表达甲基化基因（DEMGs），并将其分为4个亚组。TSS200和5'UTR被确认为差异甲基化CpG位点（DMCs）的高富集区域。DEMGs的功能富集在组蛋白H3-K27甲基化、转录后调控和DNA指导的RNA聚合酶活性过程中。通路富集显示DEMGs参与血管内皮生长因子（VEGF）信号通路、脂肪细胞因子信号通路和磷脂酰肌醇-3激酶-蛋白激酶B（PI3K-Akt）信号通路。此外，CAD患者与对照之间关键基因纤连蛋白1（FN1）、磷酸酶（PTEN）、张力蛋白同源物和RNA聚合酶III亚基A（POLR3A）的表达不一致，且与DNA甲基化水平相关。总之，我们的研究鉴定了PBLs中CAD的潜在生物标志物，并验证了FN1、PTEN和POLR3A。
