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WIREs Syst Biol Med
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miRNA regulation in the context of functional protein networks: principles and applications

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MicroRNAs (miRNAs) are small non‐coding endogenous regulatory RNAs that fine‐tune gene expression in a wide range of biological processes and diseases. miRNAs exert their function by targeting mRNAs to trigger their degradation or inhibit protein translation. The proteins encoded by the genes targeted by miRNAs may act as key components of cellular networks, thus the use of biological molecular network information for the purposes of elucidating the role of miRNAs in molecular disease mechanism is a key objective in systems biomedicine. The crosstalk layer between miRNA–target networks and functional protein is rich sources of information to explore the function of miRNAs at the system level. Characterizing the influence of miRNAs in the context of the target (protein interactors of the target) is in the early stages with potential to help better understand how miRNAs function within the cellular networks. In this article, the latest research on the cross‐talk between miRNAs and protein networks, particularly physical protein interactions and gene regulatory networks is summarized. This article also covers recent research on understanding the biology of miRNAs at the system level and defines principles of miRNA regulation of protein and gene regulatory networks. The second part of the article highlights the promise of considering the protein context of the miRNA target when searching for functional miRNA–target interactions. Some of the applications of integrating protein networks with miRNA–targets that have clinical and functional utility are described. WIREs Syst Biol Med 2014, 6:189–199. doi: 10.1002/wsbm.1251 This article is categorized under: Analytical and Computational Methods > Computational Methods Laboratory Methods and Technologies > Macromolecular Interactions, Methods Biological Mechanisms > Regulatory Biology Laboratory Methods and Technologies > RNA Methods

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Principles governing microRNA (miRNA) regulation of protein networks. The principles of miRNA regulation of protein networks are summarized in four principles. (a). Hub and bottleneck protein are more susceptible for miRNA regulation compared with non‐hub proteins. Also, there is a positive correlation between the degree of the protein and the number of the targeting miRNA. (b) protein complex components are under the regulation of single miRNA. (c) miRNAs that are coexpressed and clustered on the same loci tend to target the same biological pathway. (d) Genes that are highly regulated by transcription factors (TFs) are also highly regulated by miRNAs. Genes that have multiple TF binding sites in their promoters tend to have multiple miRNA binding sites in their 3′UTR.
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Application areas of microRNA (miRNA)‐regulated protein networks. Integrating downstream effect of miRNA targets opens several areas of functional genomic research, like predicting miRNA mode of action, identifying prognostic miRNA regulated networks, and network‐based miRNA enrichment.
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Laboratory Methods and Technologies > RNA Methods
Biological Mechanisms > Regulatory Biology
Analytical and Computational Methods > Computational Methods
Laboratory Methods and Technologies > Macromolecular Interactions, Methods

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