Role of dna methylation at herv sequence in systemic lupus erythematosus

Abstract

Previous studies reported that T cells from active SLE patients contained globally hypomethylation and demethylation at promoter of several genes which contributed to disease pathogenesis. So far there is limited information about methylation profile of retroelements in SLE. In this study, we examined and compared the methylation levels of LINE-1, Alu, HERV-E and HERV-K in normal and SLE CD4+ T lymphocytes, CD8+ T lymphocytes and B lymphocytes. Hypomethylation of LINE-1 but not Alu was found in CD4+ T lymphocytes, CD8+ T lymphocytes, and B lymphocytes of SLE patient. Strikingly, LINE-1 hypomethylation was more significantly distinguished in both CD4+ and CD8+ T lymphocytes of patients from the active SLE group. For LTR retroelements, hypomethylation of HERV-E LTR2C was observed in CD4+ T cells of active SLE. Moreover, the hypomethylation of HERV-E LTR2C was correlated with leucopenia and lymphopenia in active SLE while the hypomethylation of HERV-K LTR5_Hs in CD3+CD4+ T cells was significantly correlated with complement activity and SLEDAI score. From comprehensive analysis of genome and gene expression array, IFN-induced genes showed up-regulation in methylation sensitive gene in CD4+ T cells of SLE. However, hypomethylation at promoter region and containing of LINE-1 within gene does not explain this up-regulation. In conclusion, the hypomethylation in each lymphocyte subset of SLE was interspersed repetitive sequences (IRSs) type-specific. We also provided an evidence to propose consequence mechanism of LINE-1 hypomethylation in SLE that LINE-1 transcripts might have an effect in trans to up-regulate the IFN-induced gene. Further study to find out the functional role of IRSs hypomethylation might lead to the discovery of novel pathogenesis pathway in SLE.