title: Role of the histone H3 lysine 9 methyltransferase Suv39 h1 in maintaining Epsteinn-Barr virus latency in B95-8 cells.
abstract: The ability of Epstein-Barr Virus (EBV) to establish latent infection is associated with infectious mononucleosis and a number of malignancies. In EBV, the product of the BZLF1 gene (ZEBRA) acts as a master regulator of the transition from latency to the lytic replication cycle in latently infected cells. EBV latency is primarily maintained by hypoacetylation of histone proteins in the BZLF1 promoter by histone deacetylases. Although histone methylation is involved in the organization of chromatin domains and has a central epigenetic role in gene expression, its role in maintaining EBV latency is not well understood. Here we present evidence that the histone H3 lysine 9 (H3K9) methyltransferase suppressor of variegation 3-9 homolog 1 (Suv39 h1) transcriptionally represses BZLF1 in B95-8 cells by promoting repressive trimethylation at H3K9 (H3K9me3). Suv39 h1 significantly inhibited basal expression and ZEBRA-induced BZLF1 gene expression in B95-8 B cells. However, mutant Suv39 h1 lacks the SET domain responsible for catalytic activity of histone methyl transferase and thus had no such effect. BZLF1 transcription was augmented when Suv39 h1 expression was knocked down by siRNA in B95-8 cells, but not in Akata or Raji cells. In addition, treatment with a specific Suv39 h1 inhibitor, chaetocin, significantly enhanced BZLF1 transcription. Furthermore, chromatin immunoprecipitation assays revealed the presence of Suv39 h1 and H3K9me3 on nucleosome histones near the BZLF1 promoter. Taken together, these results suggest that Suv39 h1-H3K9me3 epigenetic repression is involved in BZLF1 transcriptional silencing, providing a molecular basis for understanding the mechanism by which EBV latency is maintained.
authors.affiliation: Department of Microbiology, Nihon University School of Dentistry, Tokyo, Japan; Division of Immunology and Pathobiology, Dental Research Center, Nihon University School of Dentistry, Tokyo, Japan.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Imai
authors.forename: Noriaki
authors.initials: N
authors.lastname: Kamio
authors.forename: Marni E
authors.initials: ME
authors.lastname: Cueno
authors.forename: Yuko
authors.initials: Y
authors.lastname: Saito
authors.forename: Hiroko
authors.initials: H
authors.lastname: Inoue
authors.forename: Ichiro
authors.initials: I
authors.lastname: Saito
authors.forename: Kuniyasu
authors.initials: K
authors.lastname: Ochiai
mesh_terms: D002460:Cell Line; D042002:Chromatin Assembly and Disassembly; D015967:Gene Expression Regulation, Viral / Q000187:drug effects / Q000502:physiology; D055785:Gene Knockdown Techniques; D004854:Herpesvirus 4, Human / Q000502:physiology*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006801:Humans; D008780:Methyltransferases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D010879:Piperazines / Q000494:pharmacology; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015534:Trans-Activators / Q000235:genetics; D017735:Virus Latency
chemical_list: C063676:BZLF1 protein, Herpesvirus 4, Human; D056572:Histone Deacetylase Inhibitors; D010879:Piperazines; D012097:Repressor Proteins; D015534:Trans-Activators; C002511:chaetocin; C407843:SUV39H1 protein, human; D008780:Methyltransferases
keywords: BZLF1; EBV; Suv39 h1; histone methylation; latency