Identification of miRNA–mRNA–TFs Regulatory Network and Crucial Pathways Involved in Tetralogy of Fallot
Identification of miRNA–mRNA–TFs Regulatory Network and Crucial Pathways Involved in Tetralogy of Fallot
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DOI：
10.3389/fgene.2020.00552
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发表时间：
2020-06
影响因子：
3.7
通讯作者：
Guoling You;Bailing Zu;Bo Wang;Q. Fu;Fen Li
中科院分区：
文献类型：
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作者：
Guoling You;Bailing Zu;Bo Wang;Q. Fu;Fen Li
法洛四联症(TOF)是最常见的青紫型先天性心脏病。然而，其发病机制尚不清楚。为了探索TOF的关键调控联系和关键途径，从国家生物技术信息中心(NCBI)基因表达总览(GEO)数据库中获得了人类TOF的基因或microRNA表达谱数据集。对TOF组和健康组的差异表达的mRNAs(DEmRNAs)和microRNAs(DEmiRs)进行数据处理，然后进行基因本体论(GO)分析和京都基因与基因组百科全书(KEGG)途径浓缩分析。然后，我们进一步构建了蛋白质相互作用(PPI)网络和模块的子网络。最后，为了研究TOF的调控网络，基于整合的数据构建了一个包括miRNAs、mRNAs和转录因子(TF)的全球三重网络。在本研究中，共发现529个DEmRNAs，其中包括115个下调的DEmRNAs和414个上调的DEmRNAs，以及7个显著上调的DemiRs，包括miR-499、miR-23b、miR-222、miR-1275、miR-93、miR-155和miR-187。此外，还鉴定了22个HUB基因和6个转录因子，包括SRF、CNOT4、SIX6、SRRM3、NELFA和ONECUT3，它们可能在TOF的分子发病机制中发挥重要作用。此外，还建立了miRNA-mRNA-Tf共调控网络，提示泛素介导的蛋白降解、能量代谢相关途径、神经发育障碍相关途径和核糖体可能参与了TOF的发病。目前的研究为TOF的调控机制网络提供了一个全面的视角，并确定了TOF遗传咨询和产前诊断的潜在分子靶点。
Tetralogy of Fallot (TOF) is the most common cyanotic congenital heart disease. However, its pathogenesis remains unknown. To explore key regulatory connections and crucial pathways underlying the TOF, gene or microRNA expression profile datasets of human TOF were obtained from the National Center for Biotechnology Information (NCBI) Gene Expression Omnibus (GEO) database. The differentially expressed mRNAs (DEmRNAs) and microRNAs (DEmiRs) between TOF and healthy groups were identified after data preprocessing, followed by Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. Then, we further constructed protein–protein interaction (PPI) network and subnetwork of modules. Ultimately, to investigate the regulatory network underlying TOF, a global triple network including miRNAs, mRNAs, and transcription factors (TFs) was constructed based on the integrated data. In the present study, a total of 529 DEmRNAs, including 115 downregulated and 414 upregulated DEmRNAs, and 7 significantly upregulated DemiRs, including miR-499, miR-23b, miR-222, miR-1275, miR-93, miR-155, and miR-187, were found between TOF and control groups. Furthermore, 22 hub genes ranked by top 5% genes with high connectivity and six TFs, including SRF, CNOT4, SIX6, SRRM3, NELFA, and ONECUT3, were identified and might play crucial roles in the molecular pathogenesis of TOF. Additionally, an miRNA–mRNA–TF co-regulatory network was established and indicated ubiquitin-mediated proteolysis, energy metabolism associated pathways, neurodevelopmental disorder associated pathways, and ribosomes might be involved in the pathogenesis of TOF. The current research provides a comprehensive perspective of regulatory mechanism networks underlying TOF and also identifies potential molecule targets of genetic counseling and prenatal diagnosis for TOF.