Uncovering MicroRNA and Transcription Factor Mediated Regulatory Networks in Glioblastoma.
Uncovering MicroRNA and Transcription Factor Mediated Regulatory Networks in Glioblastoma.
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DOI：
10.1371/journal.pcbi.1002488
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发表时间：
2012
影响因子：
4.3
通讯作者：
Zhao Z
中科院分区：
文献类型：
--
作者：
Sun J;Gong X;Purow B;Zhao Z
多形性胶质母细胞瘤(GBM)是人类最常见、最致命的脑肿瘤。最近的研究发现，小核糖核酸(miRNA，miRNA)在基底膜组织中的表达模式与正常脑组织不同，提示许多miRNA在基底膜的发病机制中起着关键作用。然而，目前还不清楚哪些miRNAs在GBM的病理过程中起核心作用，以及它们的调控作用机制。为了解决这一问题，本研究系统地探索了由miRNAs、转录因子(TF)及其影响GBM相关基因组成的主要调控形式(前馈环，FFL)，并开发了一种计算方法来构建miRNA-TF调控网络。首先，我们汇编了GBM相关的miRNAs、GBM相关基因和已知的人类转录因子。然后，我们识别了1,128个3节点FFL和805个4节点FFL，具有统计学意义。通过将这些FFL合并在一起，我们构建了一个全面的GBM特异性miRNA-Tf介导的调控网络。然后，从网络中提取了一个复合的GBM特有的调控网络。为了说明GBM特异的调控网络在识别关键的miRNA成分方面很有希望，我们特别研究了Notch信号通路的一个子网络。我们对该子网络的后续拓扑和功能分析表明，6个miRNAs(miR-124、miR-137、miR-219-5p、miR-34a、miR-9和miR-92b)可能在GBM中发挥重要作用，其中一些结果得到了先前研究的支持。在本研究中，我们开发了一个构建miRNA-Tf调控网络的计算框架，并生成了第一个针对GBM的miRNA-Tf调控网络，为进一步了解GBM中复杂的调控机制提供了宝贵的资源。对Notch信号通路中关键miRNAs的观察，以及先前研究的部分验证，表明我们基于网络的方法有望在GBM中识别新的和重要的miRNAs，并潜在地识别其他癌症。最近的一些研究表明，microRNAs(MiRNAs)在胶质母细胞瘤(GBM)的发病机制中起着关键作用。胶质母细胞瘤是人类最常见和最致命的脑肿瘤，提示miRNAs可能作为脑肿瘤和其他癌症的生物标志物在临床上有用。然而，到目前为止，miRNAs在GBM中的调控机制尚不清楚。在本研究中，我们系统地构建了miRNA和转录因子(Tf)介导的针对GBM的调控网络。为了证明GBM特异的调控网络包含可能由关键的miRNA组成的功能模块，我们提取了一个包括参与Notch信号通路的GBM相关基因的子网络。通过对Notch信号通路子网络的网络拓扑和功能分析，已经识别出几个关键的miRNAs，其中一些已经被先前的研究加强。本研究不仅为进一步的实验设计提供了新的miRNAs，而且开发了一个新的计算框架来构建特定疾病的miRNA-Tf组合调控网络。
Glioblastoma multiforme (GBM) is the most common and lethal brain tumor in humans. Recent studies revealed that patterns of microRNA (miRNA) expression in GBM tissue samples are different from those in normal brain tissues, suggesting that a number of miRNAs play critical roles in the pathogenesis of GBM. However, little is yet known about which miRNAs play central roles in the pathology of GBM and their regulatory mechanisms of action. To address this issue, in this study, we systematically explored the main regulation format (feed-forward loops, FFLs) consisting of miRNAs, transcription factors (TFs) and their impacting GBM-related genes, and developed a computational approach to construct a miRNA-TF regulatory network. First, we compiled GBM-related miRNAs, GBM-related genes, and known human TFs. We then identified 1,128 3-node FFLs and 805 4-node FFLs with statistical significance. By merging these FFLs together, we constructed a comprehensive GBM-specific miRNA-TF mediated regulatory network. Then, from the network, we extracted a composite GBM-specific regulatory network. To illustrate the GBM-specific regulatory network is promising for identification of critical miRNA components, we specifically examined a Notch signaling pathway subnetwork. Our follow up topological and functional analyses of the subnetwork revealed that six miRNAs (miR-124, miR-137, miR-219-5p, miR-34a, miR-9, and miR-92b) might play important roles in GBM, including some results that are supported by previous studies. In this study, we have developed a computational framework to construct a miRNA-TF regulatory network and generated the first miRNA-TF regulatory network for GBM, providing a valuable resource for further understanding the complex regulatory mechanisms in GBM. The observation of critical miRNAs in the Notch signaling pathway, with partial verification from previous studies, demonstrates that our network-based approach is promising for the identification of new and important miRNAs in GBM and, potentially, other cancers. Several recent studies have implicated the critical role of microRNAs (miRNAs) in the pathogenesis of glioblastoma (GBM), the most common and lethal brain tumor in humans, suggesting that miRNAs may be clinically useful as biomarkers for brain tumors and other cancers. However, to date, the regulatory mechanisms of miRNAs in GBM are unclear. In this study, we have systematically constructed miRNA and transcription factor (TF) mediated regulatory networks specific to GBM. To demonstrate that the GBM-specific regulatory network contains functional modules that may composite of critical miRNA components, we extracted a subnetwork including GBM-related genes involved in the Notch signaling pathway. Through network topological and functional analyses of the Notch signaling pathway subnetwork, several critical miRNAs have been identified, some of which have been reinforced by previous studies. This study not only provides novel miRNAs for further experimental design but also develops a novel computational framework to construct a miRNA-TF combinatory regulatory network for a specific disease.
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影响因子：
14.9
作者：
Coppe A;Ferrari F;Bisognin A;Danieli GA;Ferrari S;Bicciato S;Bortoluzzi S
通讯作者：
Bortoluzzi S
影响因子：
64.8
作者：
Baek, Daehyun;Villen, Judit;Shin, Chanseok;Camargo, Fernando D.;Gygi, Steven P.;Bartel, David P.
通讯作者：
Bartel, David P.
影响因子：
3.7
作者：
Cerami E;Demir E;Schultz N;Taylor BS;Sander C
通讯作者：
Sander C
影响因子：
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作者：
Dong H;Luo L;Hong S;Siu H;Xiao Y;Jin L;Chen R;Xiong M
通讯作者：
Xiong M
影响因子：
21.3
作者：
通讯作者：
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