title: Genome-wide DNA methylation patterns in CD4+ T cells from patients with systemic lupus erythematosus.
abstract: Systemic lupus erythematosus is a chronic-relapsing autoimmune disease of incompletely understood etiology. Recent evidence strongly supports an epigenetic contribution to the pathogenesis of lupus. To understand the extent and nature of dysregulated DNA methylation in lupus T cells, we performed a genome-wide DNA methylation study in CD4 (+) T cells in lupus patients compared to normal healthy controls. Cytosine methylation was quantified in 27,578 CG sites located within the promoter regions of 14,495 genes. We identified 236 hypomethylated and 105 hypermethylated CG sites in lupus CD4 (+) T cells compared to normal controls, consistent with widespread DNA methylation changes in lupus T cells. Of interest, hypomethylated genes in lupus T cells include CD9, which is known to provide potent T-cell co-stimulation signals. Other genes with known involvement in autoimmunity such as MMP9 and PDGFRA were also hypomethylated. The BST2 gene, an interferon-inducible membrane-bound protein that helps restrict the release of retroviral particles was also hypomethylated in lupus patients. Genes involved in folate biosynthesis, which plays a role in DNA methylation, were overrepresented among hypermethylated genes. In addition, the transcription factor RUNX3 was hypermethylated in patients, suggesting an impact on T-cell maturation. Protein-protein interaction maps identified a transcription factor, HNF4a, as a regulatory hub affecting a number of differentially methylated genes. Apoptosis was also an overrepresented ontology in these interaction maps. Further, our data suggest that the methylation status of RAB22A, STX1B2, LGALS3BP, DNASE1L1 and PREX1 correlates with disease activity in lupus patients.
authors: Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
authors: Matlock A
authors: MA
authors: Jeffries
authors: Mikhail
authors: M
authors: Dozmorov
authors: Yuhong
authors: Y
authors: Tang
authors: Joan T
authors: JT
authors: Merrill
authors: Jonathan D
authors: JD
authors: Wren
authors: Amr H
authors: AH
authors: Sawalha
mesh_terms: D000328:Adult; D000368:Aged; D015703:Antigens, CD / Q000235:genetics; D017209:Apoptosis / Q000235:genetics; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D050677:Core Binding Factor Alpha 3 Subunit / Q000235:genetics; D003596:Cytosine / Q000378:metabolism; D019175:DNA Methylation / Q000235:genetics*; D057890:Epigenomics; D005260:Female; D058851:GPI-Linked Proteins / Q000235:genetics; D055106:Genome-Wide Association Study; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000235:genetics* / Q000276:immunology*; D020780:Matrix Metalloproteinase 9 / Q000235:genetics; D008562:Membrane Glycoproteins / Q000235:genetics; D008875:Middle Aged; D011401:Promoter Regions, Genetic; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics; D060245:Tetraspanin 29; D000074010:Bone Marrow Stromal Antigen 2
chemical_list: D015703:Antigens, CD; D050677:Core Binding Factor Alpha 3 Subunit; D003596:Cytosine; D058851:GPI-Linked Proteins; D020780:Matrix Metalloproteinase 9; D008562:Membrane Glycoproteins; D020796:Receptor, Platelet-Derived Growth Factor alpha; D060245:Tetraspanin 29; C094572:BST2 protein, human; D000074010:Bone Marrow Stromal Antigen 2; C554869:CD9 protein, human; C493729:Runx3 protein, human