Abstract
BackgroundHepatitis C virus (HCV) is a major cause of chronic liver disease by infecting over 170 million people worldwide. Recent studies have shown that microRNAs (miRNAs), a class of small non-coding regulatory RNAs, are involved in the regulation of HCV infection, but their functions have not been systematically studied. We propose an integrative strategy for identifying the miRNA-mRNA regulatory modules that are associated with HCV infection. This strategy combines paired expression profiles of miRNAs and mRNAs and computational target predictions. A miRNA-mRNA regulatory module consists of a set of miRNAs and their targets, in which the miRNAs are predicted to coordinately regulate the level of the target mRNA.ResultsWe simultaneously profiled the expression of cellular miRNAs and mRNAs across 30 HCV positive or negative human liver biopsy samples using microarray technology. We constructed a miRNA-mRNA regulatory network, and using a graph theoretical approach, identified 38 miRNA-mRNA regulatory modules in the network that were associated with HCV infection. We evaluated the direct miRNA regulation of the mRNA levels of targets in regulatory modules using previously published miRNA transfection data. We analyzed the functional roles of individual modules at the systems level by integrating a large-scale protein interaction network. We found that various biological processes, including some HCV infection related canonical pathways, were regulated at the miRNA level during HCV infection.ConclusionOur regulatory modules provide a framework for future experimental analyses. This report demonstrates the utility of our approach to obtain new insights into post-transcriptional gene regulation at the miRNA level in complex human diseases.
Highlights
Hepatitis C virus (HCV) is a major cause of chronic liver disease by infecting over 170 million people worldwide
We present an integrative strategy for inferring HCV negative (HCV-)associated miRNA-mRNA regulatory modules, by combining the inverse expression relationships between miRNAs and mRNAs and computational target predictions at the sequence level
Our findings suggest that our identified regulatory modules covered various biological processes that may be perturbed during HCV infection through cellular miRNA regulation, and that the miRNA regulation may occur in a combinatorial fashion as suggested by the analysis of regulatory modules
Summary
Hepatitis C virus (HCV) is a major cause of chronic liver disease by infecting over 170 million people worldwide. Recent studies have shown that microRNAs (miRNAs), a class of small non-coding regulatory RNAs, are involved in the regulation of HCV infection, but their functions have not been systematically studied. We propose an integrative strategy for identifying the miRNA-mRNA regulatory modules that are associated with HCV infection This strategy combines paired expression profiles of miRNAs and mRNAs and computational target predictions. 170 million people worldwide and infection often leads to serious chronic liver diseases including liver cirrhosis, liver failure and hepatocellular carcinoma [2,3]. This is attributed in part to the remarkable ability of the virus to (page number not for citation purposes). To the best of our knowledge, there has not been a systematic study using high-throughput technology to analyze the role of cellular miRNAs during HCV infection
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