A Densely Interconnected Genome-Wide Network of MicroRNAs and Oncogenic Pathways Revealed Using Gene Expression Signatures
A Densely Interconnected Genome-Wide Network of MicroRNAs and Oncogenic Pathways Revealed Using Gene Expression Signatures
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DOI：
10.1371/journal.pgen.1002415
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发表时间：
2011-12-01
期刊：
影响因子：
4.5
通讯作者：
Tan, Patrick
中科院分区：
文献类型：
--
作者：
Ooi, Chia Huey;Oh, Hue Kian;Tan, Patrick
microRNAs（miRNAs）是细胞信号转导通路的重要组成部分，既可作为通路调节因子，也可作为通路靶点。目前，只有有限数量的miRNA在功能上与特定的信号通路相关。在这里，我们探讨了基因表达特征是否可以用来代表miRNA活性，并与致癌途径活性的基因组特征相结合，以高通量，全基因组范围内识别miRNA和致癌途径之间的联系。将300多个基因表达特征映射到700多个原发性肿瘤谱，我们构建了一个全基因组miRNA通路网络，预测了276种人类miRNA与26种致癌通路的关联。miRNA途径网络证实了许多先前报道的miRNA/途径关联，并发现了几种新的关联，随后通过实验验证了这些关联。在全球范围内，miRNA通路网络展示了一个小世界，但不是无标度的组织，其特征是多个不同的，紧密结合的模块，每个模块都表现出高密度的连接。然而，与仅由少数高度连接的节点（“枢纽”）代表的遗传或代谢网络不同，miRNA通路网络中的大多数节点都是高度连接的。基于序列的计算分析证实，高度互连的miRNAs可能受到共同途径的调控，以靶向相似的下游基因组，这表明共表达的miRNAs之间存在普遍和高水平的功能冗余。我们的结论是，基因表达的签名可以作为替代品的miRNA活性。我们的策略有助于发现新的miRNA通路连接的任务，因为多种正常和疾病条件下的基因表达数据是丰富的。
MicroRNAs (miRNAs) are important components of cellular signaling pathways, acting either as pathway regulators or pathway targets. Currently, only a limited number of miRNAs have been functionally linked to specific signaling pathways. Here, we explored if gene expression signatures could be used to represent miRNA activities and integrated with genomic signatures of oncogenic pathway activity to identify connections between miRNAs and oncogenic pathways on a high-throughput, genome-wide scale. Mapping >300 gene expression signatures to >700 primary tumor profiles, we constructed a genome-wide miRNA-pathway network predicting the associations of 276 human miRNAs to 26 oncogenic pathways. The miRNA-pathway network confirmed a host of previously reported miRNA/pathway associations and uncovered several novel associations that were subsequently experimentally validated. Globally, the miRNA-pathway network demonstrates a small-world, but not scale-free, organization characterized by multiple distinct, tightly knit modules each exhibiting a high density of connections. However, unlike genetic or metabolic networks typified by only a few highly connected nodes ("hubs"), most nodes in the miRNA-pathway network are highly connected. Sequence-based computational analysis confirmed that highly-interconnected miRNAs are likely to be regulated by common pathways to target similar sets of downstream genes, suggesting a pervasive and high level of functional redundancy among coexpressed miRNAs. We conclude that gene expression signatures can be used as surrogates of miRNA activity. Our strategy facilitates the task of discovering novel miRNA-pathway connections, since gene expression data for multiple normal and disease conditions are abundantly available.