FOXO3a靶向调控血管内皮细胞相关基因可变剪接的作用研究

Effect of FOXO3a Targeting on Alternative Splicing of Vascular Endothelial Cell Related Genes

目的研究血管内皮细胞在冠状动脉疾病中的作用,着重阐明转录因子叉头框蛋白O3a(forkhead box O3a,FOXO3a)调控靶标基因表达和可变剪接在血管内皮细胞损伤中的作用。方法通过在人血管内皮细胞系中过表达FOXO3a,利用转录组技术获得转录组数据。分析FOXO3a调控的潜在靶标基因的表达水平和可变剪接模式,以及这些基因的功能。结果FOXO3a过表达的HUVEC细胞中,与对照组比较,419个基因差异表达。基因本体论(gene ontology,GO)和京都基因与基因组百科全书(Kyoto encyclopedia of genes and genomes,KEGG)分析结果显示,上调基因富集在炎性信号通路,下调基因富集在代谢通路。基于转录组数据进行可变剪切分析,发现1784个可变剪切事件的模式在FOXO3a过表达组和对照组间发生显著差异。GO和KEGG分析结果显示,差异可变剪切基因富集在细胞凋亡相关通路。结论FOXO3a通过调控免疫炎症、脂类代谢和细胞凋亡相关基因的表达和可变剪接,影响血管内皮细胞凋亡,可能影响冠心病的发生。

Objective To study the role of vascular endothelial cells in coronary artery disease,focusing on the role of forkhead box O3a(FOXO3a)in regulating target gene expression and alternative splicing in vascular endothelial cell injury.Methods Transcriptome data was obtained by overexpressing FOXO3a in human vascular endothelial cell lines using transcriptome techniques.The expression levels and alternative splicing patterns of potential target genes regulated by FOXO3a were analyzed,as well as the functions of these genes.Results In HUVEC cells overexpressing FOXO3a,419genes were differentially expressed compared with the control group.The results of the geneontology(GO)and Kyoto encyclopedia of genes and genomes(KEGG)analysis showed that up-regulated genes were enriched in the inflammatory signaling pathway,while down-regulated genes were enriched in the metabolic pathway.Based on transcriptome data,alternative splicing analysis revealed significant differences in the patterns of 1784 alternative splicing events between the FOXO3a overexpression group and the control group.The results of the GO and KEGG analysis showed that differentially variable splicing genes were enriched in apoptosis-related pathways.Conclusion FOXO3a can affect the apoptosis of vascular endothelial cell by regulating the expression and alternative splicing of genes related to immune inflammation,lipid metabolism,and cell apoptosis,which may affect the occurrence of coronary heart disease.