title: Negative regulation of the interferon response by an interferon-induced long non-coding RNA.
abstract: Long non-coding RNAs (lncRNAs) play critical roles in diverse cellular processes; however, their involvement in many critical aspects of the immune response including the interferon (IFN) response remains poorly understood. To address this gap, we compared the global gene expression pattern of primary human hepatocytes before and at three time points after treatment with IFN-α. Among ∼ 200 IFN-induced lncRNAs, one transcript showed ∼ 100-fold induction. This RNA, which we named lncRNA-CMPK2, was a spliced, polyadenylated nuclear transcript that was induced by IFN in diverse cell types from human and mouse. Similar to protein-coding IFN-stimulated genes (ISGs), its induction was dependent on JAK-STAT signaling. Intriguingly, knockdown of lncRNA-CMPK2 resulted in a marked reduction in HCV replication in IFN-stimulated hepatocytes, suggesting that it could affect the antiviral role of IFN. We could show that lncRNA-CMPK2 knockdown resulted in upregulation of several protein-coding antiviral ISGs. The observed upregulation was caused by an increase in both basal and IFN-stimulated transcription, consistent with loss of transcriptional inhibition in knockdown cells. These results indicate that the IFN response involves a lncRNA-mediated negative regulatory mechanism. lncRNA-CMPK2 was strongly upregulated in a subset of HCV-infected human livers, suggesting a role in modulation of the IFN response in vivo.
authors.affiliation: Department of Biochemistry, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA.
authors.forename: Hiroto
authors.initials: H
authors.lastname: Kambara
authors.affiliation: Department of Biochemistry, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA.
authors.forename: Farshad
authors.initials: F
authors.lastname: Niazi
authors.affiliation: Divisions of Infectious and Rheumatic Diseases, Department of Medicine, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA.
authors.forename: Lenche
authors.initials: L
authors.lastname: Kostadinova
authors.affiliation: Division of Gastroenterology, Henry Ford Health System, Detroit, MI 48202, USA.
authors.forename: Dilip K
authors.initials: DK
authors.lastname: Moonka
authors.affiliation: Department of Surgery, University Hospitals Case Medical Center, Cleveland, OH 44106, USA.
authors.forename: Christopher T
authors.initials: CT
authors.lastname: Siegel
authors.affiliation: Department of Gastroenterology, University Hospitals Case Medical Center, Cleveland, OH 44106, USA.
authors.forename: Anthony B
authors.initials: AB
authors.lastname: Post
authors.affiliation: Department of Hepatology and Gene Therapy, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.
authors.forename: Elena
authors.initials: E
authors.lastname: Carnero
authors.affiliation: Department of Hepatology and Gene Therapy, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.
authors.forename: Marina
authors.initials: M
authors.lastname: Barriocanal
authors.affiliation: Department of Hepatology and Gene Therapy, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.
authors.forename: Puri
authors.initials: P
authors.lastname: Fortes
authors.affiliation: Divisions of Infectious and Rheumatic Diseases, Department of Medicine, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA.
authors.forename: Donald D
authors.initials: DD
authors.lastname: Anthony
authors.affiliation: Department of Biochemistry, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA saba.valadkhan@case.edu.
authors.forename: Saba
authors.initials: S
authors.lastname: Valadkhan
mesh_terms: D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D005786:Gene Expression Regulation; D006526:Hepatitis C / Q000235:genetics; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology*; D007371:Interferon-gamma / Q000494:pharmacology; D053612:Janus Kinases / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D051379:Mice; D062085:RNA, Long Noncoding / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D050791:STAT Transcription Factors / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D016898:Interferon-alpha; D062085:RNA, Long Noncoding; D050791:STAT Transcription Factors; D007371:Interferon-gamma; D053612:Janus Kinases