叶酸缺乏型小鼠认知障碍相关的 lncRNA-mRNA 表达谱和功能网络。

Department of Anesthesiology, The Second Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi, China.

Comb Chem High Throughput Screen. 2022;25(5):847-860. doi: 10.2174/1386207324666210208110517.

BACKGROUND

Cognitive impairment is a common neurocognitive disorder that affects the health of millions of people worldwide, related to folate deficiency.

OBJECTIVE

The present study aimed to investigate the lncRNA-mRNA functional networks associated with cognitive impairment in folate-deficient mice and elucidate their possible molecular mechanisms.

METHODS

We downloaded the gene expression profile (GSE148126) of lncRNAs and mRNAs from NCBI Gene Expression Omnibus (GEO) database. Four groups of mouse hippocampi were analyzed, including 4 months (4mo) and 18 months (18mo) of folic acid (FA) deficiency/supplementation. The differentially expressed lncRNAs (DElncRNAs) and mRNAs (DEmRNAs) were identified using gplots and heatmap packages. The functions of the DEmRNAs were evaluated using Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. The hub genes were identified by CytoHubba plugins of Cytoscape, and protein-protein interaction (PPI) network of deregulated mRNAs was performed using the STRING database. Finally, lncRNA-mRNA co-expression and competitive endogenous RNA (ceRNA) network analyses were constructed.

RESULTS

In total, we screened 67 lncRNAs with 211 mRNAs, and 89 lncRNAs with 229 mRNAs were differentially expressed in 4mo_FA and 18mo_FA deficient mice, respectively. GO analyses indicated that DEmRNAs were highly related to terms involved in binding and biological regulation. KEGG pathway analyses demonstrated that these genes were significantly enriched for renin secretion, pancreatic secretion, and AMPK signaling pathways in the 18mo_FA deficiency group. Subsequently, the top 5 hub genes were screened from the PPI network, which may be key genes with the progression of folate deficiency. Upon the lncRNA-mRNA co-expression network analysis, we identified the top 10 lncRNAs having the maximum number of connections with related mRNAs. Finally, a ceRNA network was constructed for DE lncRNAs and DEmRNAs, and several pivotal miRNAs were predicted.

CONCLUSIONS

This study identified the lncRNA-mRNA expression profiles and functional networks associated with cognitive impairment in folate-deficient mice by bioinformatics analysis, which provided support for the possible mechanisms and therapy for this disease.

背景

认知障碍是一种常见的神经认知障碍，影响着全球数百万人的健康，与叶酸缺乏有关。

目的

本研究旨在探讨叶酸缺乏性认知障碍小鼠中与认知障碍相关的长链非编码 RNA-mRNA 功能网络，并阐明其可能的分子机制。

方法

我们从 NCBI Gene Expression Omnibus（GEO）数据库中下载了长链非编码 RNA（lncRNA）和信使 RNA（mRNA）的基因表达谱（GSE148126）。分析了 4 组小鼠海马组织，包括叶酸（FA）缺乏/补充的 4 个月（4mo）和 18 个月（18mo）。使用 gplots 和 heatmap 包鉴定差异表达的 lncRNA（DElncRNA）和 mRNA（DEmRNA）。使用基因本体论（GO）和京都基因与基因组百科全书（KEGG）分析评估 DEmRNA 的功能。通过 Cytoscape 的 CytoHubba 插件鉴定枢纽基因，并使用 STRING 数据库构建调节 mRNA 的蛋白质-蛋白质相互作用（PPI）网络。最后，构建 lncRNA-mRNA 共表达和竞争性内源 RNA（ceRNA）网络分析。

结果

共筛选出 67 个 lncRNA 和 211 个 mRNA，4mo_FA 和 18mo_FA 缺乏组中分别有 89 个 lncRNA 和 229 个 mRNA 差异表达。GO 分析表明，DEmRNA 与参与结合和生物调节的术语高度相关。KEGG 通路分析表明，这些基因在 18mo_FA 缺乏组中显著富集于肾素分泌、胰腺分泌和 AMPK 信号通路。随后，从 PPI 网络中筛选出前 5 个枢纽基因，它们可能是叶酸缺乏进展的关键基因。通过 lncRNA-mRNA 共表达网络分析，我们确定了与相关 mRNAs 连接数最多的前 10 个 lncRNA。最后，构建了 DE lncRNA 和 DEmRNA 的 ceRNA 网络，并预测了几个关键的 miRNA。