title: Epigenetic profiling in CD4+ and CD8+ T cells from Graves' disease patients reveals changes in genes associated with T cell receptor signaling.
abstract: In Graves' disease (GD), a combination of genetic, epigenetic and environmental factors causes an autoimmune response to the thyroid gland, characterized by lymphocytic infiltrations and autoantibodies targeting the thyroid stimulating hormone receptor (TSHR) and other thyroid antigens. To identify the epigenetic changes involved in GD, we performed a genome-wide analysis of DNA methylation and enrichment of H3K4me3 and H3K27ac histone marks in sorted CD4+ and CD8+ T cells. We found 365 and 3322 differentially methylated CpG sites in CD4+ and CD8+ T cells, respectively. Among the hypermethylated CpG sites, we specifically found enrichment of genes involved in T cell signaling (CD247, LCK, ZAP70, CD3D, CD3E, CD3G, CTLA4 and CD8A) and decreased expression of CD3 gene family members. The hypermethylation was accompanied with decreased levels of H3K4me3 and H3K27ac marks at several T cell signaling genes in ChIP-seq analysis. In addition, we found hypermethylation of the TSHR gene first intron, where several GD-associated polymorphisms are located. Our results demonstrate an involvement of dysregulated DNA methylation and histone modifications at T cell signaling genes in GD patients.
authors.affiliation: Molecular Pathology, Institute of Biomedical and Translational Medicine, Tartu, Estonia.
authors.forename: Maia
authors.initials: M
authors.lastname: Limbach
authors.affiliation: Molecular Pathology, Institute of Biomedical and Translational Medicine, Tartu, Estonia.
authors.forename: Mario
authors.initials: M
authors.lastname: Saare
authors.affiliation: Molecular Pathology, Institute of Biomedical and Translational Medicine, Tartu, Estonia.
authors.forename: Liina
authors.initials: L
authors.lastname: Tserel
authors.affiliation: Molecular Pathology, Institute of Biomedical and Translational Medicine, Tartu, Estonia.
authors.forename: Kai
authors.initials: K
authors.lastname: Kisand
authors.affiliation: Department of Internal Medicine, University of Tartu, Tartu, Estonia; Internal Medicine Clinic, Tartu University Hospital, Tartu, Estonia.
authors.forename: Triin
authors.initials: T
authors.lastname: Eglit
authors.affiliation: Max-Planck Institute for Molecular Genetics, Berlin, Germany.
authors.forename: Sascha
authors.initials: S
authors.lastname: Sauer
authors.affiliation: Department of Medical Sciences, Molecular Medicine and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
authors.forename: Tomas
authors.initials: T
authors.lastname: Axelsson
authors.affiliation: Department of Medical Sciences, Molecular Medicine and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
authors.forename: Ann-Christine
authors.initials: AC
authors.lastname: Syvänen
authors.affiliation: Estonian Genome Center, Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia.
authors.forename: Andres
authors.initials: A
authors.lastname: Metspalu
authors.affiliation: Estonian Genome Center, Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia. Electronic address: lili.milani@ut.ee.
authors.forename: Lili
authors.initials: L
authors.lastname: Milani
authors.affiliation: Molecular Pathology, Institute of Biomedical and Translational Medicine, Tartu, Estonia. Electronic address: part.peterson@ut.ee.
authors.forename: Pärt
authors.initials: P
authors.lastname: Peterson
mesh_terms: D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D016022:Case-Control Studies; D002843:Chromatin / Q000235:genetics / Q000378:metabolism; D019295:Computational Biology / Q000379:methods; D018899:CpG Islands; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D057890:Epigenomics / Q000379:methods; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D063990:Gene Ontology; D006111:Graves Disease / Q000209:etiology* / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D006801:Humans; D011948:Receptors, Antigen, T-Cell / Q000235:genetics* / Q000378:metabolism*; D011989:Receptors, Thyrotropin / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism*
chemical_list: D002843:Chromatin; D006657:Histones; D011948:Receptors, Antigen, T-Cell; D011989:Receptors, Thyrotropin
keywords: DNA methylation; Epigenetics; Graves' disease; T cell signaling; TSHR