McAllan Alexandra L, Pillman Katherine A, Gearing Linden J, Gantier Michael P
Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, VIC 3168, Australia.
Department of Molecular and Translational Science, Monash University, Clayton, VIC 3168, Australia.
Mol Ther Nucleic Acids. 2025 May 24;36(3):102578. doi: 10.1016/j.omtn.2025.102578. eCollection 2025 Sep 9.
Despite substantial research interest over the past decade, microRNAs (miRNAs) have not yet succeeded in reaching their potential as non-invasive diagnostic biomarkers. One key hindrance to their use is the lack of disease specificity of single miRNAs, combined with variable baseline expression between individuals. In the current work, we sought to leverage variations of the stoichiometry of miRNA isoform variants, or isomiRs, to expand the pool of potential miRNA biomarkers and facilitate normalization of their expression, using one isoform to normalize expression of another from the same miRNA. Although isomiRs are often still overlooked in miRNA biomarker studies, we show that analysis at the isoform level reveals many putative biomarkers that are missed when aggregating all isomiRs by their miRNA of origin and demonstrate, as proof-of-principle, that changes in isomiR stoichiometry can act as biomarkers for inflammation and COVID-19 infection with high accuracy and precision. Our findings collectively present a case to analyze variations of isomiR stoichiometry to broaden the use of miRNAs as biomarkers, and we additionally provide a novel method of identifying putative isomiR biomarkers that offers the benefit of built-in normalization.
尽管在过去十年中受到了大量的研究关注，但微小RNA（miRNA）尚未成功发挥其作为非侵入性诊断生物标志物的潜力。其应用的一个关键障碍是单个miRNA缺乏疾病特异性，再加上个体之间基线表达的差异。在当前的研究中，我们试图利用miRNA异构体变体（即isomiRs）的化学计量变化，来扩大潜在miRNA生物标志物的范围，并促进其表达的标准化，即使用一种异构体来标准化同一miRNA中另一种异构体的表达。尽管isomiRs在miRNA生物标志物研究中常常被忽视，但我们表明，在异构体水平上进行分析会揭示许多在按其起源的miRNA汇总所有isomiRs时被遗漏的假定生物标志物，并作为原理证明表明，isomiR化学计量的变化可以高精度地作为炎症和COVID-19感染的生物标志物。我们的研究结果共同表明，分析isomiR化学计量的变化以扩大miRNA作为生物标志物的应用范围是有必要的，此外，我们还提供了一种识别假定isomiR生物标志物的新方法，该方法具有内置标准化的优点。
