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Nucleic Acids Res. 2014;42(16):10668-80. doi: 10.1093/nar/gku713. Epub 2014 Aug 13.

Negative regulation of the interferon response by an interferon-induced long non-coding RNA.

Author information

1
Department of Biochemistry, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA.
2
Divisions of Infectious and Rheumatic Diseases, Department of Medicine, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA.
3
Division of Gastroenterology, Henry Ford Health System, Detroit, MI 48202, USA.
4
Department of Surgery, University Hospitals Case Medical Center, Cleveland, OH 44106, USA.
5
Department of Gastroenterology, University Hospitals Case Medical Center, Cleveland, OH 44106, USA.
6
Department of Hepatology and Gene Therapy, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.
7
Department of Biochemistry, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA saba.valadkhan@case.edu.

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.

PMID:
25122750
PMCID:
PMC4176326
DOI:
10.1093/nar/gku713
[Indexed for MEDLINE]
Free PMC Article

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