Using context-specific effect of miRNAs to identify functional associations between miRNAs and gene signatures.
Using context-specific effect of miRNAs to identify functional associations between miRNAs and gene signatures.
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DOI：
10.1186/1471-2105-14-s12-s1
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发表时间：
2013
影响因子：
3
通讯作者：
Alhajj R
中科院分区：
文献类型：
--
作者：
Alshalalfa M;Alhajj R
MicroRNAs是一类短小的调节RNA，它作为一大批基因的转录后微调调节器，在许多细胞过程和信号通路中发挥关键作用。要了解它们的功能作用，一个有用的步骤是表征它们对靶标蛋白质上下文的影响。使用miRNA上下文特异性影响作为功能签名有望识别miRNAs与其他基因签名之间的功能关联，从而促进我们对miRNA作用模式的理解。在目前的研究中，我们利用正则化回归模型的力量来构建基因签名之间的功能关联。受miRNAs直接(计算性miRNA靶标预测)或间接(直接靶标的蛋白质伙伴)影响的基因被定义为功能性miRNA基因信号。MiRNA的直接和间接影响被定义为miRNAs的上下文特定效应，并被用来识别miRNAs对受管理的基因签名的调控效应。弹性网络回归被用来通过识别其靶标在基因列表中丰富的miRNAs来建立miRNAs的上下文特定效应与其他基因特征(疾病、途径特征)之间的功能关联。作为概念的验证，弹性网络回归被应用于前miRNA转染下调的基因列表，并成功地识别了处理后的miRNA。该模型随后被扩展到构建miRNAs与疾病之间的功能关系和途径基因列表。与miRNA直接靶标相比，整合miRNAs在蛋白质网络上的上下文特定效应揭示了在前列腺癌基因特征中更显著的miRNA浓缩。该模型确定了与前列腺癌临床变量相关的miRNAs的新列表。弹性网回归被用作构建miRNA签名和其他基因签名之间的功能关联的模型。通过整合miRNAs的下游效应来定义miRNA上下文特定的功能基因签名，显示出比单独的miRNA签名(直接靶标)更好的性能。MiRNA功能签名可以极大地促进miRNA研究，以揭示miRNA与疾病、药物或途径之间的新的功能关联。
MicroRNAs are a class of short regulatory RNAs that act as post-transcriptional fine-tune regulators of a large host of genes that play key roles in many cellular processes and signaling pathways. A useful step for understanding their functional role is characterizing their influence on the protein context of the targets. Using miRNA context-specific influence as a functional signature is promising to identify functional associations between miRNAs and other gene signatures, and thus advance our understanding of miRNA mode of action. In the current study we utilized the power of regularized regression models to construct functional associations between gene signatures. Genes that are influenced by miRNAs directly(computational miRNA target prediction) or indirectly (protein partners of direct targets) are defined as functional miRNA gene signature. The combined direct and indirect miRNA influence is defined as context-specific effects of miRNAs, and is used to identify regulatory effects of miRNAs on curated gene signatures. Elastic-net regression was used to build functional associations between context-specific effect of miRNAs and other gene signatures (disease, pathway signatures) by identifying miRNAs whose targets are enriched in gene lists. As a proof of concept, elastic-net regression was applied on lists of genes downregulated upon pre-miRNA transfection, and successfully identified the treated miRNA. This model was then extended to construct functional relationships between miRNAs and disease and pathway gene lists. Integrating context-specific effects of miRNAs on a protein network reveals more significant miRNA enrichment in prostate gene signatures compared to miRNA direct targets. The model identified novel list of miRNAs that are associated with prostate clinical variables. Elastic-net regression is used as a model to construct functional associations between miRNA signatures and other gene signatures. Defining miRNA context-specific functional gene signature by integrating the downstream effect of miRNAs demonstrates better performance compared to the miRNA signature alone (direct targets). miRNA functional signatures can greatly facilitate miRNA research to uncover new functional associations between miRNAs and diseases, drugs or pathways.