Abstract
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 language | English |
|---|---|
| Pages (from-to) | 1099-1110 |
| Number of pages | 12 |
| Journal | Cell |
| Volume | 160 |
| Issue number | 6 |
| Early online date | 12 Mar 2015 |
| DOIs | |
| Publication status | Published - 12 Mar 2015 |
Keywords
- Argonaute Proteins
- Base Sequence
- Cell Line, Tumor
- Eukaryotic Initiation Factors
- Hepacivirus
- Hepatitis C
- Humans
- Liver
- MicroRNAs
- Molecular Sequence Data
- RNA, Viral
- Virus Replication
