Epigenetic silencing of interferon-inducible genes is implicated in interferon resistance of hepatitis C virus replicon-harboring cells

Kazuhito Naka, Ken ichi Abe, Kazunori Takemoto, Hiromichi Dansako, Masanori Ikeda, Kunitada Shimotohno, Nobuyuki Kato

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

Background/Aims: We previously established hepatitis C virus (HCV) replicon-harboring cell lines possessing two interferon (IFN)-resistant phenotypes: a partially resistant phenotype (αR series) and a severely resistant phenotype (βR series). We recently found that the severe IFN resistance of the βR-series cells is caused by the functional disruption of type I IFN receptors. Here, we aimed to clarify the mechanism(s) underlying the partial IFN resistance of the αR-series cells. Methods: αR-series cells were pre-treated with 5-azacytidine to evaluate the effects of DNA demethylation on IFN resistance. cDNA microarray analysis was carried out in order to compare 1αR cells, which belong to the αR series, treated with both 5-azacytidine and IFN-α with cells treated with 5-azacytidine or IFN-α alone. Results: We found that the IFN-resistant phenotype of αR-series cells was impaired by treatment with 5-azacytidine. cDNA microarray analysis identified seven IFN-stimulated genes, which were up-regulated by 5-azacytidine treatment. We demonstrated here that the ectopic expression of each of these seven genes in 1αR cells frequently weakened the IFN resistance of these cells. Conclusions: The present results suggest that the epigenetic silencing of IFN-stimulated genes is implicated in the acquisition of a partially IFN-resistant phenotype of HCV replicon-harboring cells.

Original languageEnglish
Pages (from-to)869-878
Number of pages10
JournalJournal of Hepatology
Volume44
Issue number5
DOIs
Publication statusPublished - May 2006

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Replicon
Epigenomics
Hepacivirus
Interferons
Azacitidine
Genes
Phenotype
Microarray Analysis
Oligonucleotide Array Sequence Analysis
Interferon alpha-beta Receptor

Keywords

  • cDNA microarray
  • DNA methylation
  • Epigenetic silencing
  • HCV replicon
  • IFN resistance

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Epigenetic silencing of interferon-inducible genes is implicated in interferon resistance of hepatitis C virus replicon-harboring cells. / Naka, Kazuhito; Abe, Ken ichi; Takemoto, Kazunori; Dansako, Hiromichi; Ikeda, Masanori; Shimotohno, Kunitada; Kato, Nobuyuki.

In: Journal of Hepatology, Vol. 44, No. 5, 05.2006, p. 869-878.

Research output: Contribution to journalArticle

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AB - Background/Aims: We previously established hepatitis C virus (HCV) replicon-harboring cell lines possessing two interferon (IFN)-resistant phenotypes: a partially resistant phenotype (αR series) and a severely resistant phenotype (βR series). We recently found that the severe IFN resistance of the βR-series cells is caused by the functional disruption of type I IFN receptors. Here, we aimed to clarify the mechanism(s) underlying the partial IFN resistance of the αR-series cells. Methods: αR-series cells were pre-treated with 5-azacytidine to evaluate the effects of DNA demethylation on IFN resistance. cDNA microarray analysis was carried out in order to compare 1αR cells, which belong to the αR series, treated with both 5-azacytidine and IFN-α with cells treated with 5-azacytidine or IFN-α alone. Results: We found that the IFN-resistant phenotype of αR-series cells was impaired by treatment with 5-azacytidine. cDNA microarray analysis identified seven IFN-stimulated genes, which were up-regulated by 5-azacytidine treatment. We demonstrated here that the ectopic expression of each of these seven genes in 1αR cells frequently weakened the IFN resistance of these cells. Conclusions: The present results suggest that the epigenetic silencing of IFN-stimulated genes is implicated in the acquisition of a partially IFN-resistant phenotype of HCV replicon-harboring cells.

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