Functional characterization of the MECP2/IRAK1 lupus risk haplotype in human T cells and a human MECP2 transgenic mouse (P3319)

Abstract

Abstract Genetic polymorphism in MECP2/IRAK1 is a confirmed susceptibility locus for lupus. DNA methylation changes in T cells play a central role in the pathogenesis of lupus, and MeCp-2 is a master regulator of gene expression and is known to recruit DNA methyltransferase 1 (DNMT1) during DNA synthesis. Using human T cells from normal individuals, we demonstrate that the lupus risk variant in MECP2/IRAK1 increases MECP2 mRNA expression in stimulated T cells. By assessing DNA methylation levels at ~ 485,000 methylation sites across the genome, we further show 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. We also 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. Importantly, we demonstrate 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.