Aier School of Ophthalmology, Central South University, Changsha, China.
Aier Eye Institute, Changsha, China.
Bioengineered. 2021 Dec;12(1):7061-7078. doi: 10.1080/21655979.2021.1976502.
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 (HO) and TNFα co-treated retinal pigment epithelium (RPE) . 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.
年龄相关性黄斑变性（AMD）是一种常见的致盲性眼病。本研究旨在整合 DNA 甲基化与转录组谱，探索 AMD 的关键特征。从基因表达综合数据库（GEO，注册号：GSE135092）获取基因表达数据，从 ArrayExpress 存储库（E-MTAB-7183）获取 DNA 甲基化数据。在 AMD 患者与对照组之间共鉴定到 456 个差异表达基因（DEGs）和 4827 个基因内差异甲基化 CpG（DMC）。对 DEGs 和 DMCs 进行交集分析，鉴定到 19 个表观遗传诱导（EI）基因和 15 个表观遗传抑制（ES）基因。进行免疫细胞浸润分析以估计每个样本中不同类型免疫细胞的丰度。炎症反应和肿瘤坏死因子-α（TNFα）信号通过核因子 κB（NF-κb）的富集评分与激活的记忆 CD4 T 细胞和 M1 巨噬细胞的丰度呈正相关。随后，基于 DNA 甲基化和转录组数据构建了两个显著的随机森林分类器。通过功能表观遗传模块（FEM）分析，选择 SMAD2 和 NGFR 作为关键基因。在过氧化氢（HO）和 TNFα 共同处理的视网膜色素上皮（RPE）中验证了 SMAD2、NGFR 及其整合蛋白的表达水平。本研究结果表明，局部炎症和全身炎症宿主反应在 AMD 的发病机制中起关键作用。SMAD2 和 NGFR 为理解分子机制提供了新的视角，是开发 AMD 治疗方法的潜在治疗靶点。
