Unknown,Transcriptomics,Genomics,Proteomics

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Epigenetic regulations in the IFNM-NM-3 signalling pathway: IFNM-NM-3-mediated MHC class I upregulation on tumour cells is associated with DNA demethylation of antigen-presenting machinery genes [TC1A9_DAC]

ABSTRACT: Reversible MHC class I deficiency on tumour cells is commonly caused by coordinated silencing of antigen-presenting machinery genes and restorable by IFNM-NM-3. Here we describe association of DNA demethylation of selected antigen-presenting machinery gene regulatory regions located in the MHC genomic locus (TAP-1, TAP-2, LMP-2, LMP-7) upon IFNM-NM-3 treatment with MHC class I upregulation on tumour cells. Our novel findings demonstrate that IFNM-NM-3 acts as an epigenetic modifier upregulating the expression of antigen-presenting machinery genes through DNA demethylation. Our data also cast more light on the role of DNA methylation in tumour cell escape from specific immunity. TC-1/A9 cultured cells treated with DAC/TSA or nothing. 3 biological replicates per condition.

ORGANISM(S): Mus musculus

SUBMITTER: Milan Reinis

PROVIDER: E-GEOD-53466 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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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.

Vlková Veronika V Štěpánek Ivan I Hrušková Veronika V Šenigl Filip F Mayerová Veronika V Šrámek Martin M Šímová Jana J Bieblová Jana J Indrová Marie M Hejhal Tomáš T Dérian Nicolas N Klatzmann David D Six Adrien A Reiniš Milan M

Oncotarget 20140801 16

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 ...[more]

PMID: 25071011

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Project description:Objective: In idiopathic inflammatory myopathies (IIM) infiltration of immune cells into muscle and upregulation of MHC-I expression implies increased antigen presentation and involvement of the proteasome system. To decipher the role of immunoproteasomes in myositis, we investigated individual cell types and muscle tissues and focused on possible immune triggers. Methods: Expression of constitutive (PSMB5, -6, -7) and corresponding immunoproteasomal subunits (PSMB8, -9, -10) was analyzed by real-time RT-PCR in muscle biopsies and sorted peripheral blood cells of patients with IIM, non-inflammatory myopathies (NIM) and healthy donors (HD). Protein analysis in muscle biopsies was performed by western blot. Affymetrix HG-U133 platform derived transcriptome data from biopsies of different muscle diseases and from immune cell types as well as monocyte stimulation experiments were used for validation, coregulation and coexpression analyses. Results: Real-time RT-PCR revealed significantly increased expression of immunoproteasomal subunits (PSMB8/-9/-10) in DC, monocytes and CD8+ T-cells in IIM. In muscle biopsies, the immunosubunits were elevated in IIM compared to NIM and exceeded levels of matched blood samples. Proteins of PSMB8 and -9 were found only in IIM but not NIM muscle biopsies. Reanalysis of 78 myositis and 20 healthy muscle transcriptomes confirmed these results and revealed involvement of the antigen processing and presentation pathway. Comparison with reference profiles of sorted immune cells and healthy muscle confirmed upregulation of PSMB8 and -9 in myositis biopsies beyond infiltration related changes. This upregulation correlated highest with STAT1, IRF1 and IFNM-NM-3 expression. Elevation of T-cell specific transcripts in active IIM muscles was accompanied by increased expression of DC and monocyte marker genes and thus reflects the cell type specific involvement observed in peripheral blood. Conclusions: Immunoproteasomes seem to indicate IIM activity and suggest that dominant involvement of antigen processing and presentation may qualify these diseases exemplarily for the evolving therapeutic concepts of immunoproteasome specific inhibition. Investigation of constitutive and immunoproteasomal subunit expression in muscle tissue of patients with inflammatory and non-inflammatory myopathies These transcriptomes were used as reference signatures of different immune cell types in order to estimate the contribution of immune cell transcripts to the muscle transcriptomes investigated in the datasets GSE2044, GSE3112, GSE5370, GSE39454, GSE3307, GSE13205, GSE10685.

Dataset Information

Epigenetic regulations in the IFNM-NM-3 signalling pathway: IFNM-NM-3-mediated MHC class I upregulation on tumour cells is associated with DNA demethylation of antigen-presenting machinery genes [TC1A9_DAC]

Publications

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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