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年龄相关性黄斑变性中差异表达和甲基化基因的鉴定及共表达网络的构建

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

作者信息

Liang Gaohua, Ma Wenhao, Luo Yanni, Yin Jiayang, Hao Lili, Zhong Jingxiang

机构信息

Department of Ophthalmology, The First Affiliated Hospital of Jinan University, Guangzhou, China.

Department of Ophthalmology, Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, China.

出版信息

Ann Transl Med. 2022 Feb;10(4):223. doi: 10.21037/atm-21-7043.

DOI:10.21037/atm-21-7043
PMID:35280389
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8908173/
Abstract

BACKGROUND

Age-related macular degeneration (AMD) is the leading cause of blindness for people over 50 years old worldwide. The purpose of this study was to identify differentially expressed and methylated genes (DEMGs) and construct a co-expression network for AMD.

METHODS

Microarray expression (GSE29801 dataset) and DNA methylation (GSE102952 dataset) profiles were retrieved from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) and differentially methylated genes (DMGs) were analyzed between AMD retina tissues and normal retina tissues. A protein-protein interaction (PPI) network was constructed and hub genes were screened, followed by functional enrichment analysis. Then, weighted gene co-expression network analysis (WGCNA) was conducted. The ARPE-19 cells were maintained in a hypoxic state to construct an AMD cellular model. Enzyme-linked immunosorbent assay (ELISA) and the real-time qPCR (RT-qPCR) were performed for validation.

RESULTS

After overlapping, 16 hypermethylated and down-regulated genes and 15 hypomethylated and up-regulated genes were identified for extramacular AMD. A total of 4 hub genes (, and ) were screened for AMD in the extramacular retina. Furthermore, 13 hypermethylated and down-regulated genes and 31 hypomethylated and up-regulated genes were identified for macular AMD. Among them, 11 hub genes (, and ) were considered hub genes. The DEMGs were distinctly related with immune-related biological processes and pathways. A total of 16 co-expression modules were constructed, of which 2 significantly correlated with AMD. The genes in the 2 modules were involved in various crucial signaling pathways. The HIF1α and VEGF levels were significantly up-regulated in cell supernatant of hypoxia-induced ARPE-19 cells, indicating that the AMD cellular model was successfully established. Hub genes including CHRDL, FSTL1, and IFITM3 displayed significantly higher expression in hypoxia-induced ARPE-19 cells compared to normal cells. Greater up-regulation of CHRDL, FSTL1, and IFITM3 expression was found in hypoxia-induced ARPE-19 cells than in normal cells.

CONCLUSIONS

These findings offered several key DEMGs and pathways for AMD and constructed AMD-related co-expression modules, deepening understanding of the pathogenesis of AMD.

摘要

背景

年龄相关性黄斑变性（AMD）是全球50岁以上人群失明的主要原因。本研究的目的是鉴定差异表达和甲基化基因（DEMGs）并构建AMD的共表达网络。

方法

从基因表达综合数据库（GEO）中检索微阵列表达（GSE29801数据集）和DNA甲基化（GSE102952数据集）谱。分析AMD视网膜组织和正常视网膜组织之间的差异表达基因（DEGs）和差异甲基化基因（DMGs）。构建蛋白质-蛋白质相互作用（PPI）网络并筛选枢纽基因，随后进行功能富集分析。然后，进行加权基因共表达网络分析（WGCNA）。将ARPE-19细胞维持在低氧状态以构建AMD细胞模型。进行酶联免疫吸附测定（ELISA）和实时定量PCR（RT-qPCR）进行验证。

结果

重叠后，确定了16个高甲基化且下调的基因以及15个低甲基化且上调的基因与黄斑外AMD相关。在黄斑外视网膜中筛选出4个AMD的枢纽基因（……以及……）。此外，确定了13个高甲基化且下调的基因以及31个低甲基化且上调的基因与黄斑AMD相关。其中，11个枢纽基因（……以及……）被视为枢纽基因。DEMGs与免疫相关的生物学过程和途径明显相关。共构建了16个共表达模块，其中2个与AMD显著相关。这2个模块中的基因参与了各种关键信号通路。缺氧诱导的ARPE-19细胞的细胞上清液中HIF1α和VEGF水平显著上调，表明成功建立了AMD细胞模型。与正常细胞相比，包括CHRDL、FSTL1和IFITM3在内的枢纽基因在缺氧诱导的ARPE-19细胞中表达显著更高。缺氧诱导的ARPE-19细胞中CHRDL、FSTL1和IFITM3表达的上调幅度大于正常细胞。

结论

这些发现为AMD提供了几个关键的DEMGs和途径，并构建了与AMD相关的共表达模块，加深了对AMD发病机制的理解。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3929/8908173/5d4cf8831553/atm-10-04-223-f12.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3929/8908173/4b5f1c3afc8b/atm-10-04-223-f8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3929/8908173/6ec50369f277/atm-10-04-223-f9.jpg
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