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Epigenetic regulations in the IFNγ signalling pathway: IFNγ-mediated MHC class I upregulation on tumour cells is associated with DNA demethylation of antigen-presenting machinery genes

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    0436793 - ÚMG 2015 RIV US eng J - Journal Article
    Vlková, Veronika - Štěpánek, Ivan - Hrušková, Veronika - Šenigl, Filip - Mayerová, Veronika - Šrámek, Martin - Šímová, Jana - Bieblová, Jana - Indrová, Marie - Hejhal, Tomáš - Dérian, N. - Klatzmann, D. - Six, A. - Reiniš, Milan
    Epigenetic regulations in the IFNγ signalling pathway: IFNγ-mediated MHC class I upregulation on tumour cells is associated with DNA demethylation of antigen-presenting machinery genes.
    OncoTarget. Roč. 5, č. 16 (2014), s. 6923-35. ISSN 1949-2553
    R&D Projects: GA ČR GAP301/10/2174; GA MZd NT14461
    EU Projects: European Commission(XE) 18933 - CLINIGENE
    Grant - others:French state funds within the Investissements d’Avenir program(FR) ANR-11-IDEX-0004-02
    Institutional support: RVO:68378050
    Keywords : IFNγ signalling pathway * DNA demethylation * tumour
    Subject RIV: EB - Genetics ; Molecular Biology
    Impact factor: 6.359, year: 2014

    Downregulation of MHC class I expression on tumour cells, a common mechanism by which tumour cells can escape from specific immune responses, can be associated with coordinated silencing of antigen-presenting machinery genes. The expression of these genes can be restored by IFNγ. In this study we documented association of DNA demethylation of selected antigen-presenting machinery genes located in the MHC genomic locus (TAP-1, TAP-2, LMP-2, LMP-7) upon IFNγ treatment with MHC class I upregulation on tumour cells in several MHC class I-deficient murine tumour cell lines (TC-1/A9, TRAMP-C2, MK16 and MC15). Our data also documented higher methylation levels in these genes in TC-1/A9 cells, as compared to their parental MHC class I-positive TC-1 cells. IFNγ-mediated DNA demethylation was relatively fast in comparison with demethylation induced by DNA methyltransferase inhibitor 5-azacytidine, and associated with increased histone H3 acetylation in the promoter regions of APM genes. Comparative transcriptome analysis in distinct MHC class I-deficient cell lines upon their treatment with either IFNγ or epigenetic agents revealed that a set of genes, significantly enriched for the antigen presentation pathway, was regulated in the same manner. Our data demonstrate that IFNγ acts as an epigenetic modifier when upregulating the expression of antigen-presenting machinery genes.
    Permanent Link: http://hdl.handle.net/11104/0241959

     
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