Identification of active transcription factor and miRNA regulatory pathways in Alzheimer's disease
Identification of active transcription factor and miRNA regulatory pathways in Alzheimer's disease
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DOI：
10.1093/bioinformatics/btt423
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发表时间：
2013-10-15
期刊：
影响因子：
5.8
通讯作者：
Li, Xia
中科院分区：
文献类型：
--
作者：
Jiang, Wei;Zhang, Yan;Li, Xia
动机：阿尔茨海默病（Alzheimer's disease，AD）是一种严重的中枢神经系统退行性疾病，其可能是由调节通路的紊乱而不是单个基因的功能障碍引起的。然而，AD的病理机制尚未完全阐明。结果：在这项研究中，我们系统地分析了AD相关的mRNA和miRNA的表达谱，以及策划的转录因子（TF）和miRNA的调节，以确定活跃的TF和miRNA的调节途径在AD。通过将差异表达基因和miRNA映射到策划的TF和miRNA调控网络作为活性种子节点，我们获得了AD中潜在的活性子网络。其次，通过广度优先搜索技术，确定了潜在的活性调控途径，即TF、miRNA及其靶基因的调控级联。最后，基于已知的AD相关基因和miRNAs，超几何检验用于识别AD的活性通路。结果发现，在AD中有9条通路被显著激活。一项全面的文献综述显示，这些活性通路中的9个基因和miRNA中有8个与AD相关。此外，我们推测hsa-miR-146 a-> STAT 1-> MYC通路可能在AD的进展中发挥重要作用，这需要通过生物学实验进一步验证。因此，本研究为寻找AD中TF和miRNA的活性调控通路提供了一种有效的方法，并可容易地应用于其他复杂疾病。
Motivation: Alzheimer's disease (AD) is a severe neurodegenerative disease of the central nervous system that may be caused by perturbation of regulatory pathways rather than the dysfunction of a single gene. However, the pathology of AD has yet to be fully elucidated.Results: In this study, we systematically analyzed AD-related mRNA and miRNA expression profiles as well as curated transcription factor (TF) and miRNA regulation to identify active TF and miRNA regulatory pathways in AD. By mapping differentially expressed genes and miRNAs to the curated TF and miRNA regulatory network as active seed nodes, we obtained a potential active subnetwork in AD. Next, by using the breadth-first-search technique, potential active regulatory pathways, which are the regulatory cascade of TFs, miRNAs and their target genes, were identified. Finally, based on the known AD-related genes and miRNAs, the hypergeometric test was used to identify active pathways in AD. As a result, nine pathways were found to be significantly activated in AD. A comprehensive literature review revealed that eight out of nine genes and miRNAs in these active pathways were associated with AD. In addition, we inferred that the pathway hsa-miR-146a -> STAT1 -> MYC, which is the source of all nine significantly active pathways, may play an important role in AD progression, which should be further validated by biological experiments. Thus, this study provides an effective approach to finding active TF and miRNA regulatory pathways in AD and can be easily applied to other complex diseases.