The role of epigenetic variation in the pathogenesis of systemic lupus erythematosus

Abstract

The focus of the present review is on the extent to which epigenetic alterations influence the development of systemic lupus erythematosus. Lupus is a systemic autoimmune disease characterized by the production of autoantibodies directed at nuclear self-antigens. A DNA methylation defect in CD4+ T cells has long been observed in idiopathic and drug-induced lupus. Recent studies utilizing high-throughput technologies have further characterized the nature of the DNA methylation defect in lupus CD4+ T cells. Emerging evidence in the literature is revealing an increasingly interconnected network of epigenetic dysregulation in lupus. Recent reports describe variable expression of a number of regulatory microRNAs in lupus CD4+ T cells, some of which govern the expression of DNA methyltransferase 1. While studies to date have revealed a significant role for epigenetic defects in the pathogenesis of lupus, the causal nature of epigenetic variation in lupus remains elusive. Future longitudinal epigenetic studies in lupus are therefore needed.

Figure 1

Epigenetics of lupus CD4+ T cells. A broad DNA methylation defect is observed in lupus CD4+ T cells. Reduced expression of DNA methyltransferase 1 (DNMT1) is observed to lead to the hypomethylation and overexpression of several genes in lupus CD4+ T cells. Specifically, hypomethylation of promoter regions of CD70, CD11a, PRF1, CD40LG (CD40 ligand), and killer immunoglobulin-like receptor (KIR) genes leads to their overexpression and subsequent induction of T-cell autoreactivity. Further, overexpression of GADD45A (growth arrest and DNA-damage-inducible 45 alpha) contributes to decreased DNA methylation in lupus CD4+ T cells. There is overlap between the DNA methylation defect in lupus and other epigenetic mechanisms. Overexpression of miR-148a and miR-126 affect DNA methylation levels by directly targeting DNMT1 transcripts. miR-21 overexpression also affects DNA methylation; however, this microRNA indirectly regulates DNMT1 expression through ERK pathway signaling. Variable expression of other individual regulatory microRNAs also contributes to the disease process. Overexpression of miR-17-92 in murine T lymphocytes is observed and may affect lymphocyte stability. miRNA-155 is overexpressed in CD4+ T cells and contributes to reduced stability of regulatory T cell populations. miR-31 negatively regulates the expression of Foxp3 and has been observed to be overexpressed in murine splenocytes. Underexpression of miR-146 leads to increased type I IFN signaling in lupus CD4+ T cells. Reduced expression of miR-125a leads to increased expression of the inflammatory chemokine RANTES by reduced targeting of KLF13 transcripts. Overexpression of miR-101 has been reported in murine T lymphocytes. miR-101 has also been reported to negatively regulate EZH2, a histone methyltransferase involved in epigenetic repression. Aberrant patterns of histone modification are also observed in lupus CD4+ T cells. Reduced levels of histone 3 lysine 9 trimethylation (H3K9me3) are observed as well as reduced p300 histone acetyltransferase activity. Further, EZH2 levels are reduced in lupus CD4+ T cells. Reduced levels of the transcription factor RFX1 lead to loss of local epigenetic repression characterized by reduced levels of DNA methylation and H3K9me3 via the histone methyltransferase SUV39H1.

Figure 2

Genome-wide methylation studies in lupus. (a) Differences in promoter DNA methylation were investigated in the context of identical genetic background (that is, discordant monozygotic (MZ) twins). Javierre and colleagues [61] performed a genome-wide methylation scan investigating epigenetic differences in five pairs of monozygotic twins discordant for lupus. The study investigated these differences in white blood cells (WBCs) of patients and their related controls. The study reported variable methylation of 49 of the 807 genes investigated. Pathway analysis of these genes reveals putative functions in immune response, cell activation, and cell proliferation. The study further identifies hypomethylation and overexpression of ribosomal genes, which may correspond to increased ribosomal-autoantibody formation. (b) Jeffries and colleagues [62] investigated the methylation status of over 27,000 individual CpG dinucleotides located in promoter regions of nearly 15,000 genes. Twelve lupus cases of varying disease activity and healthy control individuals were included in the study. The study reports hypomethylation of CpG dinucleotides in 232 genes and the hypermethylation of 104 genes. Pathway analysis reveals genes involved in folate biosynthesis, a pathway related to maintenance of DNA methylation. Further, modifications of individual genes observed to be dysregulated included the hypomethylation of CD9, encoding a known activator of T cell signaling, and hypermethylation of RUNX3, which encodes a transcription factor that mediates profileration signals in lymphocytes. In both of the diagrams on the left side of each panel, empty red circles represent unmethylated CpG dinucleotides, whereas solid blue circles represent methylated CpG sites. In the lower panel, the differences in color of the gene body indicate the presence of genetic heterogeneity.