Hepatitis C virus RNA functionally sequesters miR-122

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

doi:10.1016/j.cell.2015.02.025

Hepatitis C virus RNA functionally sequesters miR-122

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

292 Citations (Scopus)

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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
Journal	Cell
Volume	160
Issue number	6
Pages (from-to)	1099-110
Number of pages	12
ISSN	0092-8674
DOIs	https://doi.org/10.1016/j.cell.2015.02.025
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

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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.",

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

author = "Luna, \{Joseph M\} and Scheel, \{Troels K H\} and Tal Danino and Shaw, \{Katharina S\} and Aldo Mele and Fak, \{John J\} and Eiko Nishiuchi and Takacs, \{Constantin N\} and Catanese, \{Maria Teresa\} and \{de Jong\}, \{Ype P\} and Jacobson, \{Ira M\} and Rice, \{Charles M\} and Darnell, \{Robert B\}",

year = "2015",

month = mar,

day = "12",

doi = "10.1016/j.cell.2015.02.025",

language = "English",

volume = "160",

pages = "1099--110",

journal = "Cell",

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TY - JOUR

T1 - Hepatitis C virus RNA functionally sequesters miR-122

AU - Luna, Joseph M

AU - Scheel, Troels K H

AU - Danino, Tal

AU - Shaw, Katharina S

AU - Mele, Aldo

AU - Fak, John J

AU - Nishiuchi, Eiko

AU - Takacs, Constantin N

AU - Catanese, Maria Teresa

AU - de Jong, Ype P

AU - Jacobson, Ira M

AU - Rice, Charles M

AU - Darnell, Robert B

PY - 2015/3/12

Y1 - 2015/3/12

N2 - 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.

AB - 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.

KW - Argonaute Proteins

KW - Base Sequence

KW - Cell Line, Tumor

KW - Eukaryotic Initiation Factors

KW - Hepacivirus

KW - Hepatitis C

KW - Humans

KW - Liver

KW - MicroRNAs

KW - Molecular Sequence Data

KW - RNA, Viral

KW - Virus Replication

UR - https://www.scopus.com/pages/publications/84924561760

U2 - 10.1016/j.cell.2015.02.025

DO - 10.1016/j.cell.2015.02.025

M3 - Journal article

C2 - 25768906

SN - 0092-8674

VL - 160

SP - 1099

EP - 1110

JO - Cell

JF - Cell

IS - 6

ER -

Hepatitis C virus RNA functionally sequesters miR-122

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