Systemic lupus erythematosus is a complex autoimmune disease caused by genetic 
and epigenetic alterations. DNA methylation abnormalities play an important role 
in systemic lupus erythematosus disease processes. MicroRNAs (miRNAs) have been 
implicated as fine-tuning regulators controlling diverse biological processes at 
the level of posttranscriptional repression. Dysregulation of miRNAs has been 
described in various disease states, including human lupus. Whereas previous 
studies have shown miRNAs can regulate DNA methylation by targeting the DNA 
methylation machinery, the role of miRNAs in aberrant CD4+ T cell DNA 
hypomethylation of lupus is unclear. In this study, by using high-throughput 
microRNA profiling, we identified that two miRNAs (miR-21 and miR-148a) 
overexpressed in CD4+ T cells from both patients with lupus and lupus-prone 
MRL/lpr mice, which promote cell hypomethylation by repressing DNA 
methyltransferase 1 (DNMT1) expression. This in turn leads to the overexpression 
of autoimmune-associated methylation-sensitive genes, such as CD70 and LFA-1, 
via promoter demethylation. Further experiments revealed that miR-21 indirectly 
downregulated DNMT1 expression by targeting an important autoimmune gene, 
RASGRP1, which mediated the Ras-MAPK pathway upstream of DNMT1; miR-148a 
directly downregulated DNMT1 expression by targeting the protein coding region 
of its transcript. Additionally, inhibition of miR-21 and miR-148a expression in 
CD4+ T cells from patients with lupus could increase DNMT1 expression and 
attenuate DNA hypomethylation. Together, our data demonstrated a critical 
functional link between miRNAs and the aberrant DNA hypomethylation in lupus 
CD4+ T cells and could help to develop new therapeutic approaches.