Global microRNA profiling reveals complex interactions among hepatic microRNA regulation, hepatitis C virus infection and interferon response
Hawwa F. Alao, Helen Cha, Stephan Chiu, Qisheng Li, T. Jake Liang
Liver diseases branch, NIH, Bethesda, MD
MicroRNAs (miRNAs) are small non-coding RNAs that fine tune gene expression to control essential biological processes through down-regulation of translation or transcription of mRNAs. Host miRNAs, like miR-122, have been shown to play an important role in hepatitis C virus (HCV) replication. HCV, on the other hand, may manipulate miRNA expression in infected hepatocytes to create a favorable host environment for productive infection and propagation. We recently conducted a genome-wide functional screen and identified an entire repertoire of cellular miRNAs that are associated with the complete life cycle of HCV. To further investigate the interactions between host miRNAs and HCV, we performed global miRNA expression analyses in both primary human hepatocytes and Huh. 7.5.1 human hepatoma cell line. Cells were infected with HCV at various time points or treated with interferon-alpha (IFNalpha) or interferon-lamda (IFN-lambda) either in the presence or absence of HCV infection. Applying the Nanostring miRNA profiling technology, we identified multiple miRNAs that were significantly regulated by HCV infection or interferon treatment. HCV treated cells showed an overall decrease in general microRNA expression at all time points, albeit several miRNAs were considerably up-regulated by HCV. These HCV-induced miRNAs include miR-122, miR-107, miR-29a-3p, miR-27b-3p and miR-301a-3p. Increased expression of miR-122 in HCVinfected cells aligns with a proviral role of the miRNA in HCV replication. Interestingly we showed that IFN-alpha generally decreased the overall miRNA expression levels, whereas IFNlambda increased the general microRNA expression, suggesting that distinct mechanisms may be engaged by these two families of IFNs to regulate miRNA profiles in hepatocytes. Among the IFN-modulated specific miRNAs are let 7b-5p, miR 425-5p, miR 140-5p, miR 1066-5p and miR 125b-5p. Conclusion: HCV infection induces a unique response in miRNA expression to facilitate productive infection. This response may result from a complex interplay among innate mechanisms, such as interferon responses, in infected hepatocytes. A comprehensive study of host miRNA expression and regulation associated with HCV infection may provide crucial insights into HCV-host interactions and mechanisms of interferon response.
The following people have nothing to disclose: Hawwa F. Alao, Helen Cha, Stephan Chiu, Qisheng Li, T. Jake Liang