Identification of the aberrantly methylated differentially expressed genes in proliferative diabetic retinopathy.

ABSTRACT

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, SERPINH1, LOX, RBP3, OTX2, RPE65, OPN1SW 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, TFDP1, 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.