Genome-Wide DNA Methylation Analysis of Systemic Lupus Erythematosus Reveals Persistent Hypomethylation of Interferon Genes and Compositional Changes to CD4+ T-cell Populations

• Published in: PLoS genetics Vol. 9; no. 8; p. e1003678
• Main Authors: Absher, Devin M., Li, Xinrui, Waite, Lindsay L., Gibson, Andrew, Roberts, Kevin, Edberg, Jeffrey, Chatham, W. Winn, Kimberly, Robert P.
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.08.2013; Public Library of Science (PLoS)
• Subjects: Antigens, CD19 - metabolism; Autoimmune diseases; B-Lymphocytes - immunology; B-Lymphocytes - metabolism; Biology; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - metabolism; Cell Lineage; CpG Islands - genetics; Deoxyribonucleic acid; DNA; DNA methylation; DNA Methylation - genetics; DNA sequencing; Epigenetics; Epigenomics; Genetic aspects; Genome, Human; Genome-wide association studies; Health aspects; Humans; Interferon; Interferons - genetics; Interferons - immunology; Lupus; Lupus Erythematosus, Systemic - genetics; Lupus Erythematosus, Systemic - immunology; Lupus Erythematosus, Systemic - pathology; Medicine; Methylation; Nucleotide sequencing; Physiological aspects; Promoter Regions, Genetic; Systemic lupus erythematosus; T cells; T-Lymphocytes, Regulatory - immunology; T-Lymphocytes, Regulatory - metabolism; United States
• ISSN: 1553-7404; 1553-7390; 1553-7404
• DOI: 10.1371/journal.pgen.1003678

Systemic lupus erythematosus (SLE) is an autoimmune disease with known genetic, epigenetic, and environmental risk factors. To assess the role of DNA methylation in SLE, we collected CD4+ T-cells, CD19+ B-cells, and CD14+ monocytes from 49 SLE patients and 58 controls, and performed genome-wide DNA methylation analysis with Illumina Methylation 450 microarrays. We identified 166 CpGs in B-cells, 97 CpGs in monocytes, and 1,033 CpGs in T-cells with highly significant changes in DNA methylation levels (p < 1 × 10(-8)) among SLE patients. Common to all three cell-types were widespread and severe hypomethylation events near genes involved in interferon signaling (type I). These interferon-related changes were apparent in patients collected during active and quiescent stages of the disease, suggesting that epigenetically-mediated hypersensitivity to interferon persists beyond acute stages of the disease and is independent of circulating interferon levels. This interferon hypersensitivity was apparent in memory, naïve and regulatory T-cells, suggesting that this epigenetic state in lupus patients is established in progenitor cell populations. We also identified a widespread, but lower amplitude shift in methylation in CD4+ T-cells (> 16,000 CpGs at FDR < 1%) near genes involved in cell division and MAPK signaling. These cell type-specific effects are consistent with disease-specific changes in the composition of the CD4+ population and suggest that shifts in the proportion of CD4+ subtypes can be monitored at CpGs with subtype-specific DNA methylation patterns.