title: 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.
abstract: 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.
authors: Department of Tumour Immunology, Institute of Molecular Genetics, Academy of Sciences of the Czech Republic, v. v. i., Prague.
authors: Veronika
authors: V
authors: Vlková
authors: Department of Tumour Immunology, Institute of Molecular Genetics, Academy of Sciences of the Czech Republic, v. v. i., Prague.
authors: Ivan
authors: I
authors: Štěpánek
authors: Department of Tumour Immunology, Institute of Molecular Genetics, Academy of Sciences of the Czech Republic, v. v. i., Prague.
authors: Veronika
authors: V
authors: Hrušková
authors: Department of Viral and Cellular Genetics, Institute of Molecular Genetics, Academy of Sciences of the Czech Republic, v. v. i., Prague.
authors: Filip
authors: F
authors: Šenigl
authors: Department of Tumour Immunology, Institute of Molecular Genetics, Academy of Sciences of the Czech Republic, v. v. i., Prague.
authors: Veronika
authors: V
authors: Mayerová
authors: Department of Tumour Immunology, Institute of Molecular Genetics, Academy of Sciences of the Czech Republic, v. v. i., Prague.
authors: Martin
authors: M
authors: Šrámek
authors: Department of Tumour Immunology, Institute of Molecular Genetics, Academy of Sciences of the Czech Republic, v. v. i., Prague.
authors: Jana
authors: J
authors: Šímová
authors: Department of Tumour Immunology, Institute of Molecular Genetics, Academy of Sciences of the Czech Republic, v. v. i., Prague.
authors: Jana
authors: J
authors: Bieblová
authors: Department of Tumour Immunology, Institute of Molecular Genetics, Academy of Sciences of the Czech Republic, v. v. i., Prague.
authors: Marie
authors: M
authors: Indrová
authors: Department of Tumour Immunology, Institute of Molecular Genetics, Academy of Sciences of the Czech Republic, v. v. i., Prague.
authors: Tomáš
authors: T
authors: Hejhal
authors: UPMC Univ Paris 06, UMR 7211, Immunology-Immunopathology-Immunotherapy (I3), Paris, France; CNRS, UMR 7211, Immunology-Immunopathology-Immunotherapy (I3), Paris, France; INSERM, UMR_S 959, Immunology-Immunopathology-Immunotherapy (I3), Paris, France; AP-HP, Hôpital Pitié-Salpêtrière, CIC-BTi Biotherapy & Département Hospitalo-Universitaire (DHU) Inflammation-Immunopathology-Biotherapy (i2B), Paris, France.
authors: Nicolas
authors: N
authors: Dérian
authors: UPMC Univ Paris 06, UMR 7211, Immunology-Immunopathology-Immunotherapy (I3), Paris, France; CNRS, UMR 7211, Immunology-Immunopathology-Immunotherapy (I3), Paris, France; INSERM, UMR_S 959, Immunology-Immunopathology-Immunotherapy (I3), Paris, France; AP-HP, Hôpital Pitié-Salpêtrière, CIC-BTi Biotherapy & Département Hospitalo-Universitaire (DHU) Inflammation-Immunopathology-Biotherapy (i2B), Paris, France.
authors: David
authors: D
authors: Klatzmann
authors: UPMC Univ Paris 06, UMR 7211, Immunology-Immunopathology-Immunotherapy (I3), Paris, France; CNRS, UMR 7211, Immunology-Immunopathology-Immunotherapy (I3), Paris, France; INSERM, UMR_S 959, Immunology-Immunopathology-Immunotherapy (I3), Paris, France; AP-HP, Hôpital Pitié-Salpêtrière, CIC-BTi Biotherapy & Département Hospitalo-Universitaire (DHU) Inflammation-Immunopathology-Biotherapy (i2B), Paris, France.
authors: Adrien
authors: A
authors: Six
authors: Department of Tumour Immunology, Institute of Molecular Genetics, Academy of Sciences of the Czech Republic, v. v. i., Prague.
authors: Milan
authors: M
authors: Reiniš
mesh_terms: D000818:Animals; D017951:Antigen Presentation / Q000235:genetics*; D019175:DNA Methylation; D015536:Down-Regulation; D044127:Epigenesis, Genetic; D005354:Fibrosarcoma / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D005805:Genes, MHC Class I; D007371:Interferon-gamma / Q000235:genetics* / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D015398:Signal Transduction; D014162:Transfection; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
chemical_list: D007371:Interferon-gamma