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Epigenetic regulation of polyomavirus JC

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 infec...

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Autores principales: Wollebo, Hassen S, Woldemichaele, Baheru, Khalili, Kamel, Safak, Mahmut, White, Martyn K
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3765676/
https://www.ncbi.nlm.nih.gov/pubmed/23971673
http://dx.doi.org/10.1186/1743-422X-10-264
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author Wollebo, Hassen S
Woldemichaele, Baheru
Khalili, Kamel
Safak, Mahmut
White, Martyn K
author_facet Wollebo, Hassen S
Woldemichaele, Baheru
Khalili, Kamel
Safak, Mahmut
White, Martyn K
author_sort Wollebo, Hassen S
collection PubMed
description 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.
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spelling pubmed-37656762013-09-08 Epigenetic regulation of polyomavirus JC Wollebo, Hassen S Woldemichaele, Baheru Khalili, Kamel Safak, Mahmut White, Martyn K Virol J Research 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. BioMed Central 2013-08-23 /pmc/articles/PMC3765676/ /pubmed/23971673 http://dx.doi.org/10.1186/1743-422X-10-264 Text en Copyright ©2013 Wollebo et al.; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research
Wollebo, Hassen S
Woldemichaele, Baheru
Khalili, Kamel
Safak, Mahmut
White, Martyn K
Epigenetic regulation of polyomavirus JC
title Epigenetic regulation of polyomavirus JC
title_full Epigenetic regulation of polyomavirus JC
title_fullStr Epigenetic regulation of polyomavirus JC
title_full_unstemmed Epigenetic regulation of polyomavirus JC
title_short Epigenetic regulation of polyomavirus JC
title_sort epigenetic regulation of polyomavirus jc
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3765676/
https://www.ncbi.nlm.nih.gov/pubmed/23971673
http://dx.doi.org/10.1186/1743-422X-10-264
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