Inferring functional miRNA-mRNA regulatory modules in epithelial-mesenchymal transition with a probabilistic topic model

Kunming University of Science and Technology, Kunming, China.
Computers in Biology and Medicine (Impact Factor: 1.24). 01/2012; 42(4):428-37. DOI: 10.1016/j.compbiomed.2011.12.011
Source: PubMed


MicroRNAs (miRNAs) play important roles in gene regulatory networks. In this paper, we propose a probabilistic topic model to infer regulatory networks of miRNAs and their target mRNAs for specific biological conditions at the post-transcriptional level, so-called functional miRNA-mRNA regulatory modules (FMRMs). The probabilistic model used in this paper can effectively capture the relationship between miRNAs and mRNAs in specific cellular conditions. Furthermore, the proposed method identifies negatively and positively correlated miRNA-mRNA pairs which are associated with epithelial, mesenchymal, and other condition in EMT (epithelial-mesenchymal transition) data set, respectively. Results on EMT data sets show that the inferred FMRMs can potentially construct the biological chain of 'miRNA→mRNA→condition' at the post-transcriptional level.

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Available from: Junpeng Zhang, Jul 25, 2014
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    • "The discovery of MRMs has demonstrated that using both sequence information and expression profiles can produce more accurate predictions. Attempts have also been made to infer functional miRNA–mRNA regulatory modules (FMRMs), which are regulatory networks of miRNAs and mRNAs for specific biological conditions [19] [20] [21] [22] [23] [24] [25] [26]. The identified FMRMs give insights into biological processes, functional regulatory interactions of many diseases and gene target therapy. "
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    ABSTRACT: Discovering the regulatory relationships between microRNAs (miRNAs) and mRNAs is an important problem that interests many biologists and medical researchers. A number of computational methods have been proposed to infer miRNA-mRNA regulatory relationships, and are mostly based on the statistical associations between miRNAs and mRNAs discovered in observational data. The miRNA-mRNA regulatory relationships identified by these methods can be both direct and indirect regulations. However, differentiating direct regulatory relationships from indirect ones is important for biologists in experimental designs. In this paper, we present a causal discovery based framework (called DirectTarget) to infer direct miRNA-mRNA causal regulatory relationships in heterogeneous data, including expression profiles of miRNAs and mRNAs, and miRNA target information. DirectTarget is applied to the Epithelial to Mesenchymal Transition (EMT) datasets. The validation by experimentally confirmed target databases suggests that the proposed method can effectively identify direct miRNA-mRNA regulatory relationships. To explore the upstream regulators of miRNA regulation, we further identify the causal feedforward patterns (CFFPs) of TF-miRNA-mRNA to provide insights into the miRNA regulation in EMT. DirectTarget has the potential to be applied to other datasets to elucidate the direct miRNA-mRNA causal regulatory relationships and to explore the regulatory patterns.
    Full-text · Article · Aug 2014 · Journal of Biomedical Informatics
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    ABSTRACT: MicroRNAs (miRNAs), a class of endogenous small noncoding RNAs, mediate posttranscriptional regulation of protein-coding genes by binding chiefly to the 3' untranslated region of target mRNAs, leading to translational inhibition, mRNA destabilization or degradation. A single miRNA concurrently downregulates hundreds of target mRNAs designated "targetome", and thereby fine-tunes gene expression involved in diverse cellular functions, such as development, differentiation, proliferation, apoptosis and metabolism. Recently, we characterized the molecular network of the whole human miRNA targetome by using bioinformatics tools for analyzing molecular interactions on the comprehensive knowledgebase. We found that the miRNA targetome regulated by an individual miRNA generally constitutes the biological network of functionally-associated molecules in human cells, closely linked to pathological events involved in cancers and neurodegenerative diseases. We also identified a collaborative regulation of gene expression by transcription factors and miRNAs in cancer-associated miRNA targetome networks. This review focuses on the workflow of molecular network analysis of miRNA targetome in silico. We applied the workflow to two representative datasets, composed of miRNA expression profiling of adult T cell leukemia (ATL) and Alzheimer's disease (AD), retrieved from Gene Expression Omnibus (GEO) repository. The results supported the view that miRNAs act as a central regulator of both oncogenesis and neurodegeneration.
    Full-text · Article · Oct 2012 · BioData Mining
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    ABSTRACT: Background: microRNAs (miRNAs) play an essential role in the post-transcriptional gene regulation in plants and animals. They regulate a wide range of biological processes by targeting messenger RNAs (mRNAs). Evidence suggests that miRNAs and mRNAs interact collectively in gene regulatory networks. The collective relationships between groups of miRNAs and groups of mRNAs may be more readily interpreted than those between individual miRNAs and mRNAs, and thus are useful for gaining insight into gene regulation and cell functions. Several computational approaches have been developed to discover miRNA-mRNA regulatory modules (MMRMs) with a common aim to elucidate miRNA-mRNA regulatory relationships. However, most existing methods do not consider the collective relationships between a group of miRNAs and the group of targeted mRNAs in the process of discovering MMRMs. Our aim is to develop a framework to discover MMRMs and reveal miRNA-mRNA regulatory relationships from the heterogeneous expression data based on the collective relationships. Results: We propose DIscovering COllective group RElationships (DICORE), an effective computational framework for revealing miRNA-mRNA regulatory relationships. We utilize the notation of collective group relationships to build the computational framework. The method computes the collaboration scores of the miRNAs and mRNAs on the basis of their interactions with mRNAs and miRNAs, respectively. Then it determines the groups of miRNAs and groups of mRNAs separately based on their respective collaboration scores. Next, it calculates the strength of the collective relationship between each pair of miRNA group and mRNA group using canonical correlation analysis, and the group pairs with significant canonical correlations are considered as the MMRMs. We applied this method to three gene expression datasets, and validated the computational discoveries. Conclusions: Analysis of the results demonstrates that a large portion of the regulatory relationships discovered by DICORE is consistent with the experimentally confirmed databases. Furthermore, it is observed that the top mRNAs that are regulated by the miRNAs in the identified MMRMs are highly relevant to the biological conditions of the given datasets. It is also shown that the MMRMs identified by DICORE are more biologically significant and functionally enriched.
    Full-text · Article · Jan 2016 · BMC Genomics