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Hepatitis C virus RNA functionally sequesters miR-122

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  • Joseph M Luna
  • Troels K H Scheel
  • Tal Danino
  • Katharina S Shaw
  • Aldo Mele
  • John J Fak
  • Eiko Nishiuchi
  • Constantin N Takacs
  • Maria Teresa Catanese
  • Ype P de Jong
  • Ira M Jacobson
  • Charles M Rice
  • Robert B Darnell
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Hepatitis C virus (HCV) uniquely requires the liver-specific microRNA-122 for replication, yet global effects on endogenous miRNA targets during infection are unexplored. Here, high-throughput sequencing and crosslinking immunoprecipitation (HITS-CLIP) experiments of human Argonaute (AGO) during HCV infection showed robust AGO binding on the HCV 5'UTR at known and predicted miR-122 sites. On the human transcriptome, we observed reduced AGO binding and functional mRNA de-repression of miR-122 targets during virus infection. This miR-122 "sponge" effect was relieved and redirected to miR-15 targets by swapping the miRNA tropism of the virus. Single-cell expression data from reporters containing miR-122 sites showed significant de-repression during HCV infection depending on expression level and site number. We describe a quantitative mathematical model of HCV-induced miR-122 sequestration and propose that such miR-122 inhibition by HCV RNA may result in global de-repression of host miR-122 targets, providing an environment fertile for the long-term oncogenic potential of HCV.

Original languageEnglish
JournalCell
Volume160
Issue number6
Pages (from-to)1099-110
Number of pages12
ISSN0092-8674
DOIs
Publication statusPublished - 12 Mar 2015

    Research areas

  • Argonaute Proteins, Base Sequence, Cell Line, Tumor, Eukaryotic Initiation Factors, Hepacivirus, Hepatitis C, Humans, Liver, MicroRNAs, Molecular Sequence Data, RNA, Viral, Virus Replication

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