title: Epigenetic regulation of polyomavirus JC.
abstract: BACKGROUND
  Polyomavirus JC (JCV) causes the CNS demyelinating disease progressive multifocal leukoencephalopathy (PML), which occurs almost exclusively in people with immune deficiencies, such as HIV-1/AIDS patients. JCV infection is very common and usually occurs early in life. After primary infection, virus is controlled by the immune system but, rarely when immune function is impaired, it can re-emerge and multiply in the astrocytes and oligodendrocytes in the brain and cause PML. Thus a central question in PML pathogenesis is the nature of the molecular mechanisms maintaining JCV in a latent state and then allowing reactivation.
  
  
  METHODS
  Since transcription can be regulated by epigenetic mechanisms including DNA methylation and histone acetylation, we investigated their role in JCV regulation by employing inhibitors of epigenetic events.
  
  
  RESULTS
  The histone deacetylase inhibitors trichostatin A (TSA) and sodium butyrate powerfully stimulated JCV early and late transcription while the DNA methylation inhibitor 5-azacytidine had no effect. Analysis of JCV mutants showed that this effect was mediated by the KB element of the JCV control region, which binds transcription factors NF-κB p65, NFAT4 and C/EBPβ and mediates stimulation by TNF-α. Stimulation of transcription by p65 was additive with TSA as was cotransfection with transcriptional coactivators/acetyltransferase p300 whereas depletion of endogenous p65 by RNA interference inhibited the effect of TSA. EMSA with a KB oligonucleotide showed p65 expression, TNF-α stimulation or TSA treatment each caused a gel shift that was further shifted by antibody to p65.
  
  
  CONCLUSIONS
  We conclude that JCV is regulated epigenetically by protein acetylation events and that these involve the NF-κB p65 binding site in the JCV control region.
authors: Department of Neuroscience, Center for Neurovirology, Temple University School of Medicine, 3500 N Broad Street, Philadelphia, PA 19140, USA.
authors: Hassen S
authors: HS
authors: Wollebo
authors: Baheru
authors: B
authors: Woldemichaele
authors: Kamel
authors: K
authors: Khalili
authors: Mahmut
authors: M
authors: Safak
authors: Martyn K
authors: MK
authors: White
mesh_terms: D002460:Cell Line; D044127:Epigenesis, Genetic; D015967:Gene Expression Regulation, Viral; D054884:Host-Pathogen Interactions; D006801:Humans; D007577:JC Virus / Q000235:genetics* / Q000502:physiology; D014775:Virus Activation; D017735:Virus Latency
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