The upregulation of genomic imprinting DLK1-Dio3 miRNAs in lupus-prone mice is associated with DNA hypomethylation (BA4P.133)

Epigenetic factors such as DNA methylation and microRNAs (miRNAs) regulation are now increasingly recognized as vital contributors to lupus pathogenesis. Our recent studies revealed a large cluster of miRNAs, which is located at the genomic imprinted DLK1-Dio3 domain was dramatically increased in splenocytes from MRL- lpr mice when compared to control MRL mice. In this study, we found that MRL- lpr mice have reduced DNA methylation levels in whole splenocytes and also in purified splenic CD4 + T and CD19 + B cells when compared to MRL control, which was associated with the upregulation of DLK1-Dio3 miRNAs in lpr lupus cells. DNA demethylation treatment with 5-Aza-2’-deoxycytidine significantly increased DLK1-Dio3 miRNAs in splenic cells (especially Con A-activated cells) from MRL mice, but not MRL- lpr mice. This data further confirmed the contribution of DNA hypomethylation to the augmented expression of DLK1-Dio3 miRNAs in lupus splenic cells. Although the contribution of DLK1-Dio3 miRNAs to autoimmune disease remains unknown, our preliminary data revealed that inhibition of selected DLK1-Dio3 miRNA such as miR-379 reduced LPS-induced IFNγ in MRL- lpr splenocytes, suggesting a role of miR-379 in the regulation of inflammation. Together, our data is the first to show DNA methylation regulation of genomic imprinting DLK1-Dio3 miRNAs in autoimmune lupus, which may provide novel insight into epigenetic mechanisms in lupus pathogenesis.