Sun Xiaohan, Zhang Junying
School of Computer Science and Technology, Xidian University, Xi'an, Shaanxi, P. R. China.
College of Mathematics and Information Science, Weinan Normal University, Weinan, Shaanxi, P. R. China.
PLoS One. 2016 Jun 3;11(6):e0156324. doi: 10.1371/journal.pone.0156324. eCollection 2016.
Past research on pathogenesis of a complex disease suggests that differentially expressed message RNAs (mRNAs) can be noted as biomarkers of a disease. However, significant miRNA-mediated regulation change might also be more deep underlying cause of a disease. In this study, a miRNA-mediated regulation module is defined based on GO terms (Gene Ontology terms) from which dysfunctional modules are identified as the suspected cause of a disease. A miRNA-mediated regulation module contains mRNAs annotated to a GO term and MicroRNAs (miRNAs) which regulate the mRNAs. Based on the miRNA-mediated regulation coefficients estimated from the expression profiles of the mRNA and the miRNAs, a SW (single regulation-weight) value is then designed to evaluate the miRNA-mediated regulation change of an mRNA, and the modules with significantly differential SW values are thus identified as dysfunctional modules. The approach is applied to Chromophobe renal cell carcinoma and it identifies 70 dysfunctional miRNA-mediated regulation modules from initial 4381 modules. The identified dysfunctional modules are detected to be comprehensive reflection of chromophobe renal cell carcinoma. The proposed approach suggests that accumulated alteration in miRNA-mediated regulation might cause functional alterations, which further cause a disease. Moreover, this approach can also be used to identify diffentially miRNA-mediated regulated mRNAs showing more comprehensive underlying association with a disease than differentially expressed mRNAs.
以往关于复杂疾病发病机制的研究表明，差异表达的信使核糖核酸（mRNA）可作为疾病的生物标志物。然而，显著的微小RNA（miRNA）介导的调控变化可能也是疾病更深层次的潜在原因。在本研究中，基于基因本体论（GO）术语定义了一个miRNA介导的调控模块，从中识别出功能失调的模块作为疾病的疑似病因。一个miRNA介导的调控模块包含注释到一个GO术语的mRNA以及调控这些mRNA的微小RNA（miRNA）。基于从mRNA和miRNA的表达谱估计的miRNA介导的调控系数，设计了一个SW（单调控权重）值来评估mRNA的miRNA介导的调控变化，因此具有显著差异SW值的模块被识别为功能失调模块。该方法应用于肾嫌色细胞癌，从最初的4381个模块中识别出70个功能失调的miRNA介导的调控模块。检测到所识别的功能失调模块是肾嫌色细胞癌的全面反映。所提出的方法表明，miRNA介导的调控中的累积改变可能导致功能改变，进而导致疾病。此外，该方法还可用于识别差异miRNA介导调控的mRNA，与差异表达的mRNA相比，其显示出与疾病更全面的潜在关联。
