Zhao Boyan, Jiang Xiaofan
Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
Front Neurol. 2022 Apr 11;13:852013. doi: 10.3389/fneur.2022.852013. eCollection 2022.
Ischemic cerebral infarction (ICI) is a fatal neurovascular disorder. A bioinformatics approach based on single-cell and bulk RNA-seq analyses was applied to investigate the pathways and genes involved in ICI and study the expression profile of these genes.
First, the aberrantly regulated "small-molecule ribonucleic acids" [microRNA (miRNAs)] and messenger RNAs (mRNAs) were analyzed using transcriptome data from the ischemic brain infarction dataset of the Gene Expression Omnibus (GEO) database. In mouse cerebrovascular monocytes, the single-cell regulatory network inference and clustering (SCENIC) workflow was used to identify key transcription factors (TFs). Then, the two miRNA-TF-mRNA interaction networks were constructed. Moreover, the molecular complex detection (MCODE) extracted the core sub-networks and identified the important TFs within these sub-networks. Finally, whole blood samples were collected for validation of the expression of critical molecules in ICI.
We identified four cell types and 266 regulons in mouse cerebrovascular monocytes using SCENIC analysis. Moreover, 112 differently expressed miRNAs and 3,780 differentially expressed mRNAs were identified. We discovered potential biomarkers in ICI by building a miRNA-TF-mRNA interaction network. The hsa-miR-518-5p/hsa-miR-3135b/REL/SOD2 was found to play a potential role in ICI progression. The expression of REL and superoxide dismutase 2 (SOD2) was significantly elevated in the ICI group in the clinical cohort ( < 0.05). Furthermore, a REL expression was elevated in endothelial cells and fibroblasts at the single-cell level, indicating that REL is a cell-specific regulon. Functional enrichment analyses revealed that REL is primarily engaged in neurotransmitter activity and oxidative phosphorylation.
Our research uncovered novel biomarkers for ICI of neurovascular disease. The hsa-miR-518-5p/hsa-miR-3135b may regulate the REL/SOD2 pathway in ICI progression.
缺血性脑梗死（ICI）是一种致命的神经血管疾病。应用基于单细胞和批量RNA测序分析的生物信息学方法，研究ICI中涉及的信号通路和基因，并研究这些基因的表达谱。
首先，使用基因表达综合数据库（GEO）中缺血性脑梗死数据集的转录组数据，分析异常调控的“小分子核糖核酸”（即微小RNA，miRNA）和信使核糖核酸（mRNA）。在小鼠脑血管单核细胞中，采用单细胞调控网络推断和聚类（SCENIC）工作流程来识别关键转录因子（TF）。然后，构建两个miRNA-TF-mRNA相互作用网络。此外，分子复合物检测（MCODE）提取核心子网，并识别这些子网内的重要TF。最后，采集全血样本以验证ICI中关键分子的表达。
通过SCENIC分析，我们在小鼠脑血管单核细胞中鉴定出4种细胞类型和266个调控子。此外，还鉴定出112个差异表达的miRNA和3780个差异表达的mRNA。通过构建miRNA-TF-mRNA相互作用网络，我们发现了ICI中的潜在生物标志物。发现hsa-miR-518-5p/hsa-miR-3135b/REL/SOD2在ICI进展中可能发挥潜在作用。在临床队列中，ICI组中REL和超氧化物歧化酶2（SOD2）的表达显著升高（<0.05）。此外，在单细胞水平上，内皮细胞和成纤维细胞中REL表达升高，表明REL是一种细胞特异性调控子。功能富集分析显示，REL主要参与神经递质活性和氧化磷酸化。
我们的研究发现了神经血管疾病ICI的新型生物标志物。hsa-miR-518-5p/hsa-miR-3135b可能在ICI进展中调节REL/SOD2信号通路。
