Twin DNA Methylation Profiling Reveals Flare-Dependent Interferon Signature and B Cell Promoter Hypermethylation in Systemic Lupus Erythematosus

Constance J. Ulff-Møller*, Fazila Asmar, Yi Liu, Anders J. Svendsen, Florence Busato, Kirsten Grønbæk, Jörg Tost, Søren Jacobsen

*Corresponding author for this work

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Abstract

Objective: Systemic lupus erythematosus (SLE) has limited monozygotic twin concordance, implying a role for pathogenic factors other 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 1 SLE-affected twin. Methods: Peripheral blood obtained from 15 SLE-affected twin pairs (6 monozygotic and 9 dizygotic) was processed using density-gradient centrifugation for the granulocyte fraction. CD4+ T cells, monocytes, and B cells were further isolated using magnetic beads. Genome-wide DNA methylation was analyzed using Infinium HumanMethylation450K BeadChips. When comparing probes from SLE-affected twins and co-twins, differential DNA methylation was considered statistically significant when the P value was less than 0.01 and biologically relevant when the median DNA methylation difference was >7%. Findings were validated by pyrosequencing and replicated in an independent case–control sample. Results: In paired analyses of twins discordant for SLE restricted to the gene promoter and start region, we identified 55, 327, 247, and 1,628 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 who experienced a disease flare within the past 2 years. In contrast to what was observed in the other cell types, differentially methylated CpGs in B cells were predominantly hypermethylated, and the most important upstream regulators included TNF and EP300. Conclusion: Hypomethylation of interferon-regulated genes occurs in all major cellular compartments in SLE-affected twins. The observed B cell promoter hypermethylation is a novel finding with potential significance in SLE pathogenesis.

Original languageEnglish
JournalArthritis & Rheumatology
Volume70
Issue number6
Pages (from-to)878-890
ISSN2326-5191
DOIs
Publication statusPublished - Jun 2018

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