Integrated Analysis of DNA methylation and transcriptome profile to identify key features of age-related macular degeneration

Abstract

Age-related macular degeneration (AMD) is a common vision-threatening disease. The current study sought to integrate DNA methylation with transcriptome profile to explore key features in AMD. Gene expression data were obtained from the Gene Expression Omnibus (GEO, accession ID: GSE135092) and DNA methylation data were obtained from the ArrayExpress repository (E-MTAB-7183). A total of 456 differentially expressed genes (DEGs) and 4827 intragenic differentially methylated CpGs (DMCs) were identified between AMD and controls. DEGs and DMCs were intersected and 19 epigenetically induced (EI) genes and 15 epigenetically suppressed (ES) genes were identified. Immune cell infiltration analysis was performed to estimate the abundance of different types of immune cell in each sample. Enrichment scores of inflammatory response and tumor necrosis factor-alpha (TNFα) signaling via nuclear factor kappa B (NF-κb) were positively correlated with abundance of activated memory CD4 T cells and M1 macrophages. Subsequently, two significant random forest classifiers were constructed based on DNA methylation and transcriptome data. SMAD2 and NGFR were selected as key genes through functional epigenetic modules (FEM) analysis. Expression level of SMAD2, NGFR and their integrating proteins was validated in hydrogen peroxide (H 2 O 2 ) and TNFα co-treated retinal pigment epithelium (RPE) in vitro. The findings of the current study showed that local inflammation and systemic inflammatory host response play key roles in pathogenesis of AMD. SMAD2 and NGFR provide new insight in understanding the molecular mechanism and are potential therapeutic targets for development of AMD therapy.

DNA methylation in diabetic retinopathy: pathogenetic role and potential therapeutic targets

“…For example, DNA methylation has been proven to maintain specific gene expression patterns that vary by cell type in retinal cells, such as photoreceptors and nonphotoreceptor cells [29]. On the other hand, aberrant DNA methylation is related to retinal diseases, including age-related macular degeneration (AMD) [30], DR [31] and retinitis pigmentosa [32].…”

Epigenetics and Degenerative Retinal Diseases: Prospects for New Therapeutic Approaches

“…A recent bioinformatic study identified 456 differentially expressed genes and 4827 intra-genic differentially methylated CpGs between ARMD and controls. 32 Because intragenic sites may represent important structural determinants of chromatin, or be the loci of a variety of noncoding RNAs, these methylation sites may reveal another layer of genome regulation. Using surgically excised fibrovascular membranes from patients with proliferative DR, 132 genes were found to be hypomethylated and increased in expression, and 172 genes were hypermethylated and decreased in expression.…”

“…The alternative, studying postmortem tissue also has disadvantages, namely the variable loss of cells and the possibility of postmortem changes. A recent bioinformatic study identified 456 differentially expressed genes and 4827 intra-genic differentially methylated CpGs between ARMD and controls 32 . Because intragenic sites may represent important structural determinants of chromatin, or be the loci of a variety of noncoding RNAs, these methylation sites may reveal another layer of genome regulation.…”

Contribution of Interleukin-17A to Retinal Degenerative Diseases

“…It has been reported that there were 456 differentially expressed genes (DEGs) and 4827 differentially methylated CpGs (DMCs) in the RPE samples of 26 AMD patients and 105 normal people in the GEO and Array Express databases. Enrichment analysis showed that up-regulated genes got involved in IL-17 signaling pathway in AMD ( 107 ). In terms of experiments, RPE was induced by fungi to induce different natural immune responses.…”