Integrated bioinformatics analysis of aberrantly-methylated differentially-expressed genes and pathways in age-related macular degeneration

Abstract

Background: Age-related macular degeneration (AMD) represents the leading cause of visual impairment in the aging population. The goal of this study was to identify aberrantly-methylated, differentially-expressed genes (MDEGs) in AMD and explore the involved pathways via integrated bioinformatics analysis. Methods: Data from expression profile GSE29801 and methylation profile GSE102952 were obtained from the Gene Expression Omnibus database. We analyzed differentially-methylated genes and differentially-expressed genes using R software. Functional enrichment and protein-protein interaction (PPI) network analysis were performed using the R package and Search Tool for the Retrieval of Interacting Genes online database. Hub genes were identified using Cytoscape. Results: In total, 827 and 592 genes showed high and low expression, respectively, in GSE29801; 4117 hyper-methylated genes and 511 hypo-methylated genes were detected in GSE102952. Based on overlap, we categorized 153 genes as hyper-methylated, low-expression genes (Hyper-LGs) and 24 genes as hypo-methylated, high-expression genes (Hypo-HGs). Four Hyper-LGs (CKB, PPP3CA, TGFB2, SOCS2) overlapped with AMD risk genes in the Public Health Genomics and Precision Health Knowledge Base. KEGG pathway enrichment analysis indicated that Hypo-HGs were enriched in the calcium signaling pathway, whereas Hyper-LGs were enriched in sphingolipid metabolism. In GO analysis, Hypo-HGs were enriched in fibroblast migration, membrane raft, and coenzyme binding, among others. Hyper-LGs were enriched in mRNA transport, nuclear speck, and DNA binding, among others. In PPI network analysis, 23 nodes and two edges were established from Hypo-HGs, and 151 nodes and 73 edges were established from Hyper-LGs. Hub genes (DHX9, MAPT, PAX6) showed the greatest overlap.(Continued on next page)

Urinary Mass Spectrometry Profiles in Age-Related Macular Degeneration

“…In particular, differences in urinary levels of sphingosine, a sphingolipid, were observed. This is also in agreement with a recent study on differentially expressed genes in AMD combining microarray information from RPE-choroid, retinal tissue, and blood samples, which identified an enrichment in the sphingolipid pathway [31]. Sphingolipids are a structurally diverse class of lipids that play an important role in cell membranes, but also participate in signal transduction and cell recognition, representing versatile signaling molecules that regulate multiple physiological and pathological processes [32].…”

Identification of differentially expressed and methylated genes and construction of a co-expression network in age-related macular degeneration

“…Meanwhile, greater up-regulation of CHRDL, FSTL1, and IFITM3 expression was found in hypoxia-induced ARPE-19 cells than in normal cells (Figure 12C,12D). in AMD in previous studies (12,15); however, these studies have lacked external validation. In this study, we validated the expression of DEMGs in the E-MTAB-7183 dataset.…”

“…The GSE29801 dataset was based on the GPL4133 platform, composed of 27 normal extramacular retina samples, 31 AMD extramacular retina samples, 28 normal macular retina samples, and 32 AMD macular retina samples (2). The GSE102952 dataset included 9 control retina tissues and 9 AMD retina tissues on the GPL13534 platform (12,15).…”

Potential epigenetic molecular regulatory networks in ocular neovascularization

“…On the one hand, hypoxia increased HIF-1 binding site (HBS) methylation, decreased HIF-1 DNA binding, promoted erythropoietin expression, and induced revascularization growth (Wenger et al, 1998); on the other hand, hypoxia can induce HBS demethylation of the VEGF gene promoter, increase HIF-1 on the binding properties of VEGF gene promoters, promote hypoxic induced VEGF gene transactive and VEGF accumulation (Pisani et al, 2018). In neovascular AMD, or early AMD, DNA methylation has shifted (Oliver et al, 2015;Shen et al, 2020). Hypoxia boosted the synthesis of interleukin 17 receptor C (IL-17RC) mRNA in hypoxia-induced retinal pigment epithelium (RPE) cells by boosting the demethylation of the IL-17RC promoter; promoting choroidal neovascularization by a synergistic action of IL-17RC and VEGF (Alivand, Sabouni, and Soheili 2016).…”