Epigenetic Variability in Systemic Lupus Erythematosus: What We Learned from Genome-Wide DNA Methylation Studies

Abstract

Purpose of review: DNA methylation has emerged as an important contributing factor in the pathogenesis of systemic lupus erythematosus (SLE). Here, we describe the DNA methylation patterns identified in SLE and how these epigenetic changes can influence disease susceptibility, clinical heterogeneity, and disease flares.

Recent findings: Several genome-wide DNA methylation studies have been recently completed in SLE. Important observations include robust demethylation of interferon-regulated genes, which is consistent across all cell types studied to date, and is independent of disease activity. This interferon epigenetic signature was shown to precede interferon transcription signature in SLE, suggesting it might be an early event in the disease process. Recent studies also revealed DNA methylation changes specific for renal and skin involvement in SLE, providing a proof of principle for a value of DNA methylation studies in exploring mechanisms of specific disease manifestations, and potentially as prognostic biomarkers. Inherited ethnicity-specific DNA methylation patterns have also been shown to possibly contribute to differences in SLE susceptibility between populations. Finally, a recent study revealed that DNA methylation levels at IFI44L can accurately distinguish SLE patients from healthy controls, and from patients with other autoimmune diseases, promising to be the first epigenetic diagnostic marker for SLE. Genome-wide DNA methylation studies in SLE have provided novel insights into disease pathogenesis, clinical heterogeneity, and disease flares. Further studies promise to reveal novel diagnostic, prognostic, and therapeutic targets for SLE.

Keywords: Autoimmune diseases; Environmental; Epigenetics; Gene expression regulation; Interferon signature; Lupus; Methylation; SLE; Susceptibility; T cells.

Fig. 1

Venn diagrams showing the number of differentially methylated genes in SLE compared to healthy controls among different immune cell subsets. The size of the circles corresponds with the total number of genes significantly hypo- or hypermethylated between SLE cases and controls in each immune cell subset. Each color represents one cell subset, i.e., T cells (blue), B cells (red), monocytes (green), and neutrophils (yellow). Data are from the Supplementary Materials of Coit et al. 2013 [24], Absher et al. 2013 [25], and Coit et al. 2015 [26]

Fig. 2

Gene Ontology (GO) functional annotation analysis showing the main biological processes associated with hypomethylated genes in SLE. Results from Panther GO term analysis for the most significant hypomethylated genes in each immune cell subset are shown. The y-axis represents fold enrichment measured as the percent of hypomethylated genes in each Gene Ontology term. Data are from the Supplementary Materials of Coit et al. 2013 [24], Absher et al. 2013 [25], and Coit et al. 2015 [26]

Fig. 3

Gene Ontology (GO) functional annotation analysis showing the main biological processes associated with hypermethylated genes in SLE. Results from Panther GO term analysis for the most significant hypermethylated genes in each immune cell subset are shown. The y-axis represents fold enrichment measured as the percent of hypermethylated genes in each Gene Ontology term. Data are from the Supplementary Materials of Coit et al. 2013 [24], Absher et al. 2013 [25], and Coit et al. 2015 [26]

Fig. 4

Postulated epigenetic model of SLE flares based on genome-wide DNA methylation data and associated bioinformatics analyses in naïve CD4⁺ T cells in SLE. Reproduced from “Epigenetic reprogramming in naïve CD4+ T cells favoring T cell activation and non-Th1 effector T cell immune response as an early event in lupus flares” by Patrick Coit, Mikhail G. Dozmorov, Joan T. Merrill, W. Joeseph McCune, Kathleen Maksimowics-McKinnon, Jonathan D. Wren, Amr H. Sawalha, September 1, 2016, with permission from BMJ Publishing Group Ltd.