3 years ago

Twin DNA methylation profiling reveals flare-dependent interferon signature and B-cell promoter hypermethylation in systemic lupus erythematosus

Søren Jacobsen, Jörg Tost, Fazila Asmar, Anders J Svendsen, Kirsten Grønbæk, Constance J Ulff-Møller, Yi Liu, Florence Busato
Objective Systemic lupus erythematosus (SLE) has limited monozygotic (MZ) twin concordance, implying a role for other pathogenic factors than genetic variation, such as epigenetic changes. Using the disease discordant twin model, we investigated genome-wide DNA methylation changes in sorted CD4+ T-cells, monocytes, granulocytes and B-cells in twin pairs with at least one SLE-affected twin. Methods Peripheral blood from 15 SLE twin pairs (six MZ, nine dizygotic (DZ)) was processed using gradient density centrifugation for the granulocyte fraction. CD4+ T-cells, monocytes and B-cells were further isolated using magnetic beads. Genome-wide DNA methylation was analysed using Infinium HumanMethylation450K BeadChips. Probes with a p-value <0.01 between SLE twins and co-twins were considered statistically significant and a median DNA methylation difference >7% biologically relevant. Findings were validated using pyrosequencing and replicated in an independent case-control sample. Results In paired analyses of discordant SLE twins restricted to the gene promoter and start region, we identified 55, 327, 247 and 1628 genes with differentially methylated CpGs in CD4+ T-cells, monocytes, granulocytes and B-cells, respectively. All cell types displayed marked hypomethylation in interferon-regulated genes, such as IFI44L, PARP9 and IFITM1, which was more pronounced in twins with flare within the past two years. In contrast to the other cell types, differentially methylated CpGs in B-cells were predominantly hypermethylated, where the most important upstream regulators included TNF and EP300. Conclusion Hypomethylation of interferon-regulated genes occurs in all major cellular compartments in SLE twins. The observed B-cell promoter hypermethylation is a novel finding with potential significance for SLE pathogenesis. This article is protected by copyright. All rights reserved.

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.1002/art.40422

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