环状 RNA 网络分析揭示 AP-1 转录因子组件可能成为阿尔茨海默病的生物标志物。

ceRNA Network Analysis Reveals AP-1 Transcription Factor Components as Potential Biomarkers for Alzheimer’s Disease.

机构信息

Department of Laboratory Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030 China.

Department of General Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

出版信息

Curr Alzheimer Res. 2022;19(5):387-406. doi: 10.2174/1567205019666220613142303.

DOI:10.2174/1567205019666220613142303

PMID:35702791

Abstract

BACKGROUND

Alzheimer's disease (AD) is a progressive neurodegenerative disease affecting the elderly, characterized by decreased cognitive function. Non-coding RNAs contribute to AD pathogenesis.

OBJECTIVE

To identify potential therapeutic targets for AD, competing endogenous RNA (ceRNA) networks were constructed using the hippocampus of 6-month-old amyloid precursor protein/ presenilin 1 double transgenic (APP/PS1) and wild-type mice.

METHODS

RNA-seq data (GSE158995), generated from the hippocampus of APP/PS1 and wild-type mice, were analyzed with the limma R package to identify significantly differentially expressed mRNAs and circRNAs (DEMs and DECs, respectively). DEM Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed using Enrichr (https://maayanlab.cloud/Enrichr/). Correlations between DEMs and DECs were determined using the ggcorrplot R package. Main clusters and hub DEMs were selected using the STRING database and Cytoscape software. ceRNA interactions were predicted with the miRTarbase and Starbase tools and constructed with the ggalluvial R package and Cytoscape software. ceRNA networks were validated using the quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and Western blot.

RESULTS

198 DEMs and 90 DECs were differentially expressed in APP/PS1 vs. wild-type hippocampus. DEM GO analysis revealed significant enrichment in transcription regulation, which was subdivided into three main clusters: transcription regulation, synaptic plasticity, and protein refolding. Within the transcription regulation cluster, AP-1 transcription factor components serve as hub genes. The mmu_circ_0001787(circGLCE)/miR-339-5p/Junb and mmu_circ_0001899(circFAM120C)/ miR-181a-5p/Egr1 ceRNA networks were established based on qRT-PCR and Western blot analysis.

CONCLUSION

Two AP-1 transcription factor component-related ceRNA networks, circGLCE/miR- 339-5p/Junb and circFAM120C/miR-181a-5p/Egr1, were constructed using a mouse model of AD. These ceRNA networks may contribute to transcription regulation in AD and provide potential biomarkers for AD diagnosis and treatment.

摘要

背景

阿尔茨海默病（AD）是一种影响老年人的进行性神经退行性疾病，其特征是认知功能下降。非编码 RNA 参与 AD 的发病机制。

目的

为了寻找 AD 的潜在治疗靶点，我们构建了淀粉样前体蛋白/早老素 1 双转基因（APP/PS1）和野生型小鼠海马的竞争内源性 RNA（ceRNA）网络。

方法

使用 limma R 包分析来自 APP/PS1 和野生型小鼠海马的 RNA-seq 数据（GSE158995），以鉴定显著差异表达的 mRNAs 和 circRNAs（分别为 DEMs 和 DECs）。使用 Enrichr（https://maayanlab.cloud/Enrichr/）对 DEM Gene Ontology（GO）和 Kyoto Encyclopedia of Genes and Genomes（KEGG）分析进行分析。使用 ggcorrplot R 包确定 DEMs 和 DECs 之间的相关性。使用 STRING 数据库和 Cytoscape 软件选择主要聚类和枢纽 DEMs。使用 miRTarbase 和 Starbase 工具预测 ceRNA 相互作用，并使用 ggalluvial R 包和 Cytoscape 软件构建 ceRNA 网络。使用定量逆转录-聚合酶链反应（qRT-PCR）和 Western blot 验证 ceRNA 网络。

结果

APP/PS1 与野生型海马相比，有 198 个 DEMs 和 90 个 DECs 差异表达。DEM GO 分析显示转录调控显著富集，进一步细分为三个主要聚类：转录调控、突触可塑性和蛋白质重折叠。在转录调控聚类中，AP-1 转录因子成分作为枢纽基因。基于 qRT-PCR 和 Western blot 分析，建立了 mmu_circ_0001787（circGLCE）/miR-339-5p/Junb 和 mmu_circ_0001899（circFAM120C）/miR-181a-5p/Egr1 ceRNA 网络。