探讨血清microRNA(miR)和miR相互作用在RA发病机制中的作用机制。
初治活动性RA患者血清中差异表达的miRs(DEmiRs)(NARAPs,n=9,分为三个池)与健康对照(HC,n=15,分为五个池),用Agilent人miR微阵列分析鉴定。使用miRTarBase和分子复合物检测算法分析了RA的表观遗传和致病信号通路模块中的候选驱动基因。这些DEmiR在RA发病机制中的相互作用组进一步通过基因本体论和京都基因和基因组百科全书进行表征。
三个上调的DEmiR(hsa-miR-187-5p,-4532,-4516)和八个下调的DEmiR(hsa-miR-125a-3p,-575,-191-3p,-6865-3p,-197-3p,-6886-3p,-1237-3p,-4436b-5p)在NARAP中鉴定。来自异质实验验证来源的相互作用组学分析产生了1719个miR-靶相互作用,包含5.67%的强实验证据和94.33%的弱实验证据。基因本体论和基因和基因组的京都百科全书分析分配了感染模块中上调的DEmiR和免疫信号通路中下调的DEmiR。具体来说,这些DEmiR揭示了肠道微生物群系失调在感染-炎症-免疫网络中对T细胞活化的重要贡献,IL-17,Toll样受体,TNF,Janus激酶-信号转导和转录激活因子,破骨细胞分化途径和IgA的产生对RA的主动发病机制。
我们基于实验的NARAPs血清DEmiRs相互作用组学研究揭示了RA感染-炎症-免疫网络中新型临床相关miRs相互作用。这些结果为了解miR网络在RA发病机制中的综合功能以及循环miR作为早期病因性RA诊断的生物标志物的应用提供了宝贵的资源。
To characterize serum microRNA (miR) and the miR
interactome of active RA patients in RA aetiology and pathogenesis.
The differentially expressed miRs (DEmiRs) in serum of naïve active RA patients (NARAPs, n = 9, into three pools) vs healthy controls (HCs, n = 15, into five pools) were identified with Agilent human miR microarray analysis. Candidate driver genes in epigenetic and pathogenic signalling pathway modules for RA were analysed using miRTarBase and a molecular complex detection algorithm. The
interactome of these DEmiRs in RA pathogenesis were further characterized with gene ontology and Kyoto Encyclopaedia of Genes and Genomes.
Three upregulated DEmiRs (hsa-miR-187-5p, -4532, -4516) and eight downregulated DEmiRs (hsa-miR-125a-3p, -575, -191-3p, -6865-3p, -197-3p, -6886-3p, -1237-3p, -4436b-5p) were identified in NARAPs. Interactomic analysis from heterogeneous experimentally validated sources yielded 1719 miR-target interactions containing 5.67% strong and 94.33% less strong experimental evidence. Gene ontology and Kyoto Encyclopaedia of Genes and Genomes analyses allocated the upregulated DEmiRs in the infection modules and the downregulated DEmiRs in the immune signalling pathways. Specifically, these DEmiRs revealed the significant contributions of the intestinal microbiome dysbiosis in the infection-inflammation-immune network for activation of T cells, immune pathways of IL-17, Toll-like receptor, TNF, Janus kinase-signal transducer and activator of transcription, osteoclast cell differentiation pathway and IgA production to the active RA pathogenesis.
Our experiment-based interactomic
study of DEmiRs in serum of NARAPs revealed novel clinically relevant miRs interactomes in the infection-inflammation-immune network of RA. These results provide valuable resources for understanding the integrated function of the miR network in RA pathogenesis and the application of circulating miRs as biomarkers for early aetiologic RA diagnosis.