Identification of the aberrantly methylated differentially expressed genes in proliferative diabetic retinopathy
Identification of the aberrantly methylated differentially expressed genes in proliferative diabetic retinopathy
复制标题
增殖性糖尿病视网膜病变异常甲基化差异表达基因的鉴定
DOI：
10.1016/j.exer.2020.108141
复制
发表时间：
2020-10-01
影响因子：
3.4
通讯作者：
Luo, Yan
中科院分区：
文献类型：
--
作者：
Miao, Aiwen;Lu, Jing;Luo, Yan
糖尿病视网膜病变（DR）是糖尿病最常见的并发症。增殖性 DR (PDR) 是 DR 的更高级阶段，可导致严重视力受损甚至失明。然而，PDR的确切病理机制仍不清楚。 DNA 甲基化在包括 PDR 在内的多种疾病的发生和进展中发挥着重要作用。本研究的目的是确定异常甲基化的差异表达基因（DEG）作为 PDR 的潜在治疗靶点。基因表达微阵列数据集GSE60436和甲基化分析微阵列数据集GSE57362用于确定PDR中异常甲基化的DEG，利用正常视网膜作为对照，并使用PDR患者的纤维血管膜（FVM）作为PDR样本。随后对所选基因进行功能术语和信号通路富集分析。此外，构建蛋白质-蛋白质相互作用（PPI）网络以确定枢纽基因，并分析转录因子（TF）和目标枢纽基因的网络。总共发现 132 个低甲基化基因在 PDR 中上调，而 172 个高甲基化基因被发现下调。低甲基化上调基因被发现富集在“细胞-基质粘附”、“粘附连接”、“细胞粘附分子结合”和“细胞外基质受体相互作用”等通路中。同时，高甲基化下调基因在“视觉感知”、“突触前”和“突触小泡周期”等通路中富集。基于PPI分析，总共鉴定出8个中心基因：CTGF、SERPINHI、LOX、RBP3、OTX2、RPE65、OPNISW和NRL。据推测，这些基因的异常甲基化可能与 PDR 可能的病理生理学有关。 TEDP1 是一个重要的转录因子，被发现与基因-TF 网络中的中心基因具有最密切的相互作用。总之，本研究利用生物信息学分析确定了 PDR 中 DNA 甲基化和基因表达之间的关联，并确定了在不久的将来可能成为 PDR 潜在基于甲基化的诊断和治疗靶点的中心基因。
Diabetic retinopathy (DR) is the most common complication of diabetes. Proliferative DR (PDR) is a more advanced stage of DR, which can cause severe impaired vision and even blindness. However, the precise pathological mechanisms of PDR remain unknown. DNA methylation serves an important role in the initiation and progression of numerous types of disease including PDR. The purpose of this study was to identify the aberrantly methylated differentially expressed genes (DEGs) as potential therapeutic targets of PDR. The gene expression microarray dataset GSE60436 and the methylation profiling microarray dataset GSE57362 were used to determine the aberrantly methylated DEGs in PDR, utilizing normal retinas as controls and fibrovascular membranes (FVMs) in patients with PDR as PDR samples. The functional term and signaling pathway enrichment analysis of the selected genes were subsequently performed. In addition, protein-protein interaction (PPI) networks were constructed to determine the hub genes, and the network of transcriptional factor (TF) and target hub genes was also analyzed. In total, 132 hypomethylated genes were found to be upregulated, whereas 172 hypermethylated genes were discovered to be downregulated in PDR. The hypomethylated upregulated genes were found to be enriched in the pathways, such as "cell-substrate adhesion", "adherens junction", "cell adhesion molecule binding" and "extracellular matrix receptor interactions". Meanwhile, the hypermethylated downregulated genes were enriched in the pathways, such as "visual perception", "presynapse" and the "synaptic vesicle cycle". Based on the PPI analysis, a total of eight hub genes were identified: CTGF, SERPINHI, LOX, RBP3, OTX2, RPE65, OPNISW and NRL. It was hypothesized that the aberrant methylation of these genes might be related to the possible pathophysiology of PDR. An important transcriptional factor, TEDP1, was discovered to share the closest interactions with the hub genes from the gene-TF network. In conclusion, the present study identified an association among DNA methylation and gene expression in PDR using bioinformatics analysis, and identified the hub genes which might be potential methylation-based diagnosis and treatment targets for PDR in the near future.