Functional characterization of the MECP2/IRAK1 lupus risk haplotype in human T cells and a human MECP2 transgenic mouse

Abstract

Genetic polymorphism in MECP2/IRAK1 on chromosome Xq28 is a confirmed and replicated susceptibility locus for lupus. High linkage disequilibrium in this locus suggests that both MECP2 and IRAK1 are candidate genes for the disease. DNA methylation changes in lupus T cells play a central role in the pathogenesis of lupus, and MeCp-2 (encoded by MECP2) is a master regulator of gene expression and is also known to recruit DNA methyltransferase 1 (DNMT1) during DNA synthesis. Using human T cells from normal individuals with either the lupus risk or the lupus protective haplotype in MECP2/IRAK1, we demonstrate that polymorphism in this locus increases MECP2 isoform 2 mRNA expression in stimulated but not unstimulated T cells. By assessing DNA methylation levels across over 485,000 methylation sites across the entire genome, we further demonstrate that the lupus risk variant in this locus is associated with significant DNA methylation changes, including in the HLA-DR and HLA-DQ loci, as well as interferon-related genes such as IFI6, IRF6, and BST2. Further, using a human MECP2 transgenic mouse, we show that overexpression of MECP2 alters gene expression in stimulated T cells. This includes overexpression of Eif2c2 that regulates the expression of multiple microRNAs (such as miR-21), and the histone demethylase Jhdm1d. In addition, we show that MECP2 transgenic mice develop antinuclear antibodies. Our data suggest that the lupus associated variant in the MECP2/IRAK1 locus has the potential to affect all 3 epigenetic mechanisms: DNA methylation, microRNA expression, and histone modification. Importantly, these data support the notion that variants within the MECP2 gene can alter DNA methylation in other genetic loci including the HLA and interferon-regulated genes, thereby providing evidence for genetic-epigenetic interaction in lupus.

Association between PDCD1, CTLA4, and MECP2 gene polymorphisms and systemic lupus erythematosus in the Chinese Northern Han

“…DNA methylation-sensitive genes are overexpressed in SLE (Jones et al, 1998) and MECP2 is critical in the transcriptional suppression of methylationsensitive genes (Koelsch et al, 2013), which makes MECP2 an attractive candidate gene for SLE. (Sawalha et al, 2008) confirmed the association between SLE and all eight SNPs within the MECP2 gene including rs2075596, which has previously been reported in European SLE patients and controls in a Korean population.…”

Influenza A induces dysfunctional immunity and death in MeCP2-overexpressing mice

“…Scale bar: 200 μm for large images, and 50 μm for insets. reports (7,18,19), and suggests that the adaptive immune response is markedly impaired in the context of MeCP2 overexpression. We have also identified multiple other pathologic processes during infection in MeCP2…”

“…In mice, it was shown that MeCP2 overexpression leads to development of anti-nuclear antibodies (18). In patients, deficiency of IgA and IgG 2 and excessive levels of IgG 1 and IgG 3 were found, in addition to an elevated acute-phase response (19).…”

Roles of Methyl-CpG Binding Protein 2 in Immune Function

“…This was postulated to explain a failure to clear infections in patients. Another group observed that MeCP2 overexpressing mice naturally develop anti-nuclear antibodies, which are associated with autoimmune disease (Koelsch et al, 2013). An analysis of the immune status in patients did not…”

“…However, evidence suggests that MeCP2 is not only related to Rett syndrome and MeCP2 duplication syndrome, but may also contribute to primary immunologic disorders, such as systemic lupus erythematosus (SLE) (Kaufman et al, 2013;Koelsch et al, 2013;Sawalha et al, 2008;Webb et al, 2009), primary Sjogren's syndrome (Cobb et al, 2010), systemic sclerosis (Carmona et al, 2013), and rheumatoid arthritis (Han et al, 2013).…”