title: The CD4(+) T cell methylome contributes to a distinct CD4(+) T cell transcriptional signature in Mycobacterium bovis-infected cattle.
abstract: We hypothesised that epigenetic regulation of CD4(+) T lymphocytes contributes to a shift toward a dysfunctional T cell phenotype which may impact on their ability to clear mycobacterial infection. Combined RNA-seq transcriptomic profiling and Reduced Representation Bisulfite Sequencing identified 193 significantly differentially expressed genes and 760 differentially methylated regions (DMRs), between CD4(+) T cells from M. bovis infected and healthy cattle. 196 DMRs were located within 10 kb of annotated genes, including GATA3 and RORC, both of which encode transcription factors that promote TH2 and TH17 T helper cell subsets respectively. Gene-specific DNA methylation and gene expression levels for the TNFRSF4 and Interferon-γ genes were significantly negatively correlated suggesting a regulatory relationship. Pathway analysis of DMRs identified enrichment of genes involved in the anti-proliferative TGF-β signaling pathway and TGFB1 expression was significantly increased in peripheral blood leukocytes from TB-infected cattle. This first analysis of the bovine CD4(+) T cell methylome suggests that DNA methylation directly contributes to a distinct gene expression signature in CD4(+) T cells from cattle infected with M. bovis. Specific methylation changes proximal to key inflammatory gene loci may be critical to the emergence of a non-protective CD4(+) T cell response during mycobacterial infection in cattle.
authors: Animal &Bioscience Research Department, Teagasc, Grange, Co. Meath, Ireland.|Comparative Immunology Group, School of Biochemistry and Immunology &School of Medicine, Trinity Biomedical Research Institute, Trinity College Dublin, Ireland.
authors: Rachael
authors: R
authors: Doherty
authors: Animal &Bioscience Research Department, Teagasc, Grange, Co. Meath, Ireland.|Comparative Immunology Group, School of Biochemistry and Immunology &School of Medicine, Trinity Biomedical Research Institute, Trinity College Dublin, Ireland.
authors: Ronan
authors: R
authors: Whiston
authors: Animal &Bioscience Research Department, Teagasc, Grange, Co. Meath, Ireland.
authors: Paul
authors: P
authors: Cormican
authors: Animal &Bioscience Research Department, Teagasc, Grange, Co. Meath, Ireland.
authors: Emma K
authors: EK
authors: Finlay
authors: Livestock Improvement Corporation, 605 Ruakura Rd, Newstead, Hamilton, New Zealand.
authors: Christine
authors: C
authors: Couldrey
authors: Central Veterinary Research Laboratories, Department of Agriculture, Food and the Marine, Longtown, Co. Kildare, Ireland.
authors: Colm
authors: C
authors: Brady
authors: Comparative Immunology Group, School of Biochemistry and Immunology &School of Medicine, Trinity Biomedical Research Institute, Trinity College Dublin, Ireland.
authors: Cliona
authors: C
authors: O'Farrelly
authors: Animal &Bioscience Research Department, Teagasc, Grange, Co. Meath, Ireland.
authors: Kieran G
authors: KG
authors: Meade
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000502:physiology*; D002417:Cattle; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D050990:GATA3 Transcription Factor / Q000235:genetics; D007371:Interferon-gamma / Q000235:genetics*; D009163:Mycobacterium bovis / Q000276:immunology*; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000235:genetics; D053262:Receptors, OX40 / Q000235:genetics*; D015398:Signal Transduction; D058504:Th17 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology; D059467:Transcriptome; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D014380:Tuberculosis, Bovine / Q000276:immunology*
chemical_list: D050990:GATA3 Transcription Factor; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D053262:Receptors, OX40; D016212:Transforming Growth Factor beta; D007371:Interferon-gamma