Systematic exploration of autonomous modules in noisy microRNA-target networks for testing the generality of the ceRNA hypothesis.
Systematic exploration of autonomous modules in noisy microRNA-target networks for testing the generality of the ceRNA hypothesis.
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DOI：
10.1186/1471-2164-15-1178
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发表时间：
2014-12-24
期刊：
影响因子：
4.4
通讯作者：
Yip KY
中科院分区：
文献类型：
--
作者：
Yip DK;Pang IK;Yip KY
在竞争性内源性RNA（ceRNA）假说中，不同的转录本通过竞争其共同的靶向microRNA（miRNAs）进行通信。个别例子已经清楚地表明了ceRNA在基因调控和癌症生物学中的功能重要性。目前尚不清楚一般而言ceRNA在多大程度上调控基因表达水平。研究这个问题的一个主要障碍是miRNA-靶网络中相互交织的连接，这使得很难分离单个miRNA的作用。在这里，我们提出了一种计算方法，用于将复杂的miRNA-靶标网络分解为称为microRNA-target biclusters（MTB）的大部分自主模块。每个MTB含有相对少量的密集连接的miRNA和mRNA，与其他miRNA和mRNA的连接很少。因此，每个MTB可以单独分析，与其他MTB的串扰最小。我们的方法不同于以前的方法，通过不对表达模式进行任何预先假设来寻找miRNA靶网络中的模块，从而为测试ceRNA假设提供客观信息。我们发现，在MTB中的miRNA和mRNA的表达水平比随机的miRNA-mRNA对和其他验证和预测的miRNA-target对显着更反相关，证明了MTB的生物学相关性。我们进一步表明，在各种各样的参数设置下，相同MTB中的mRNA之间的表达存在广泛的相关性，并且即使在控制共调节效应时，这种相关性仍然存在，这表明这些mRNA之间存在潜在的广泛表达缓冲，这与ceRNA假设一致。最后，我们还提出了MTB在miRNA功能注释中的潜在用途。MTB可用于帮助鉴定自主的miRNA靶模块，用于实验性地测试ceRNA假设的一般性。所鉴定的模块也可用于测试一般miRNA-靶网络的其他性质。本文的在线版本（doi：10.1186/1471-2164-15-1178）包含补充材料，可供授权用户使用。
In the competing endogenous RNA (ceRNA) hypothesis, different transcripts communicate through a competition for their common targeting microRNAs (miRNAs). Individual examples have clearly shown the functional importance of ceRNA in gene regulation and cancer biology. It remains unclear to what extent gene expression levels are regulated by ceRNA in general. One major hurdle to studying this problem is the intertwined connections in miRNA-target networks, which makes it difficult to isolate the effects of individual miRNAs. Here we propose computational methods for decomposing a complex miRNA-target network into largely autonomous modules called microRNA-target biclusters (MTBs). Each MTB contains a relatively small number of densely connected miRNAs and mRNAs with few connections to other miRNAs and mRNAs. Each MTB can thus be individually analyzed with minimal crosstalk with other MTBs. Our approach differs from previous methods for finding modules in miRNA-target networks by not making any pre-assumptions about expression patterns, thereby providing objective information for testing the ceRNA hypothesis. We show that the expression levels of miRNAs and mRNAs in an MTB are significantly more anti-correlated than random miRNA-mRNA pairs and other validated and predicted miRNA-target pairs, demonstrating the biological relevance of MTBs. We further show that there is widespread correlation of expression between mRNAs in same MTBs under a wide variety of parameter settings, and the correlation remains even when co-regulatory effects are controlled for, which suggests potential widespread expression buffering between these mRNAs, which is consistent with the ceRNA hypothesis. Lastly, we also propose a potential use of MTBs in functional annotation of miRNAs. MTBs can be used to help identify autonomous miRNA-target modules for testing the generality of the ceRNA hypothesis experimentally. The identified modules can also be used to test other properties of miRNA-target networks in general. The online version of this article (doi:10.1186/1471-2164-15-1178) contains supplementary material, which is available to authorized users.
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