Recent work from our group includes characterizing the DNA methylome in lupus using an epigenome-wide approach, resulting in the identification of novel candidate differentially methylated genes that may play a role in the pathogenesis of this disease. Our genome-wide DNA methylation studies coupled with concomitant gene expression analysis demonstrated for the first time that naïve CD4+ T cells in lupus are epigenetically poised for pathologic levels of type-1 interferon-regulated gene expression. This work provided the first mechanistic explanation for type-1 interferon hyper-responsiveness in autoimmunity, and identified a novel pathogenic role for DNA methylation changes in lupus. Other related recent work from our group includes a detailed description of the DNA methylome in normal human CD4+ T cells, and characterized and established novel genomic features to distinguish transcriptionally “repressive” from “non-repressive” DNA methylation in human. We also identified DNA methylation changes that are uniquely present in lupus patients with renal involvement, and characterized the T cell DNA methylome of skin involvement in lupus. More recent work from our group uncovered inherited ethnicity-specific CD4+ T cell DNA methylation changes that promote a chromatin architecture more permissive to autoimmunity in African-Americans, suggesting that DNA methylation changes might influence lupus susceptibility across populations.
T cells in lupus are epigenetically poised for a type I interferon response
Our data suggest a model whereby interferon-regulated genes are epigenetically poised to respond to type-I interferon upon T cell activation, and provide evidence for an epigenetic architecture favoring, and providing an explanation for, type-I interferon hyper-responsiveness to in lupus.
Ethnicity-specific DNA methylation caused by cis-acting polymorphisms that disrupt CpG sites
CpG-SNP rs55661361 is a methylation sensitive locus in the gene NRGN that has a significant difference in allele frequency (a) between African (YRI) and European (CEU) populations. The most frequent allele in African populations creates an unmethylated CpA locus, (b,c) obliterating methylation in people with both “A” alleles. This change results in distinct levels of methylation stratified by genetic background, contributing to ethnicity-related differences in autoimmune disease manifestations. (Source: Coit et al. Epigenetics &Chromatin 2015.)