Changes in epigenetic regulation of CD4+ T lymphocytesin biliary atresia.

Biliary atresia (BA) is a virus-induced autoimmune disease associated with abnormal DNA methylation patterns that contribute to disease presentation. This study examined DNA methylation patterns, changes to genes associated with methylation regulation, and changes to the autoimmune-related gene interferon gamma (IFN-γ) in CD4+ T cells from BA patients. We demonstrated that genomic DNA isolated from CD4+ T cells harvested from infants presenting with BA were hypomethylated relative to healthy controls. In addition, DNA methyltransferase (DNMT1) and DNMT3a mRNA levels were significantly lower in BA CD4+ T cells compared with controls and methyl-DNA-binding domain proteins (MBD1) mRNA expression (but not MBD4 detected at higher levels in BA patients), which was significantly lower in CD4+ T cells from BA infants than in controls. DNMT1 expression positively correlated with global DNA methylation in BA CD4+ T cells. IFN-γ mRNA expression levels in BA patients were also significantly increased, and the IFN-γ gene promoter region was hypomethylated in BA CD4+ T cells compared with controls and negatively correlated with DNA methylation. These data suggest that methylation changes in CD4+ cells may contribute to BA disease presentation and progression by affecting the expression of genes associated with autoimmunity.