title: Hepatitis C virus RNA functionally sequesters miR-122.
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.
authors.affiliation: Laboratory of Virology and Infectious Disease, Center for the Study of Hepatitis C, The Rockefeller University, New York, NY 10065, USA; Laboratory of Molecular Neuro-Oncology and Howard Hughes Medical Institute, The Rockefeller University, New York, NY 10065, USA.
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Luna
authors.affiliation: Laboratory of Virology and Infectious Disease, Center for the Study of Hepatitis C, The Rockefeller University, New York, NY 10065, USA; Copenhagen Hepatitis C Program (CO-HEP), Department of Infectious Disease and Clinical Research Centre, Copenhagen University Hospital, Hvidovre, and Department of International Health, Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, DK-2200 Copenhagen N, Denmark.
authors.forename: Troels K H
authors.initials: TK
authors.lastname: Scheel
authors.affiliation: Laboratory of Virology and Infectious Disease, Center for the Study of Hepatitis C, The Rockefeller University, New York, NY 10065, USA; Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Tal
authors.initials: T
authors.lastname: Danino
authors.affiliation: Laboratory of Virology and Infectious Disease, Center for the Study of Hepatitis C, The Rockefeller University, New York, NY 10065, USA.
authors.forename: Katharina S
authors.initials: KS
authors.lastname: Shaw
authors.affiliation: Laboratory of Molecular Neuro-Oncology and Howard Hughes Medical Institute, The Rockefeller University, New York, NY 10065, USA.
authors.forename: Aldo
authors.initials: A
authors.lastname: Mele
authors.affiliation: Laboratory of Molecular Neuro-Oncology and Howard Hughes Medical Institute, The Rockefeller University, New York, NY 10065, USA.
authors.forename: John J
authors.initials: JJ
authors.lastname: Fak
authors.affiliation: Laboratory of Virology and Infectious Disease, Center for the Study of Hepatitis C, The Rockefeller University, New York, NY 10065, USA.
authors.forename: Eiko
authors.initials: E
authors.lastname: Nishiuchi
authors.affiliation: Laboratory of Virology and Infectious Disease, Center for the Study of Hepatitis C, The Rockefeller University, New York, NY 10065, USA; Laboratory of Cellular Biophysics, The Rockefeller University, New York, NY 10065, USA.
authors.forename: Constantin N
authors.initials: CN
authors.lastname: Takacs
authors.affiliation: Laboratory of Virology and Infectious Disease, Center for the Study of Hepatitis C, The Rockefeller University, New York, NY 10065, USA.
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Catanese
authors.affiliation: Laboratory of Virology and Infectious Disease, Center for the Study of Hepatitis C, The Rockefeller University, New York, NY 10065, USA; Center for the Study of Hepatitis C, Division of Gastroenterology and Hepatology, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Ype P
authors.initials: YP
authors.lastname: de Jong
authors.affiliation: Center for the Study of Hepatitis C, Division of Gastroenterology and Hepatology, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Ira M
authors.initials: IM
authors.lastname: Jacobson
authors.affiliation: Laboratory of Virology and Infectious Disease, Center for the Study of Hepatitis C, The Rockefeller University, New York, NY 10065, USA. Electronic address: ricec@rockefeller.edu.
authors.forename: Charles M
authors.initials: CM
authors.lastname: Rice
authors.affiliation: Laboratory of Molecular Neuro-Oncology and Howard Hughes Medical Institute, The Rockefeller University, New York, NY 10065, USA; New York Genome Center, 101 Avenue of the Americas, New York, NY 10013, USA. Electronic address: darnelr@rockefeller.edu.
authors.forename: Robert B
authors.initials: RB
authors.lastname: Darnell
mesh_terms: D060565:Argonaute Proteins / Q000378:metabolism; D001483:Base Sequence; D045744:Cell Line, Tumor; D039642:Eukaryotic Initiation Factors / Q000378:metabolism; D016174:Hepacivirus / Q000235:genetics / Q000378:metabolism*; D006526:Hepatitis C / Q000378:metabolism* / Q000821:virology*; D006801:Humans; D008099:Liver / Q000378:metabolism / Q000821:virology; D035683:MicroRNAs / Q000378:metabolism*; D008969:Molecular Sequence Data; D012367:RNA, Viral / Q000737:chemistry / Q000378:metabolism*; D014779:Virus Replication
chemical_list: C115848:AGO1 protein, human; D060565:Argonaute Proteins; D039642:Eukaryotic Initiation Factors; C531907:MIRN122 microRNA, human; D035683:MicroRNAs; D012367:RNA, Viral