Increased Set1 binding at the promoter induces aberrant epigenetic alterations and up-regulates cyclic adenosine 5′-monophosphate response element modulator alpha in systemic lupus erythematosus

Background: Up-regulated cyclic adenosine 5'-monophosphate response element modulator alpha (CREM alpha) which can inhibit IL-2 and induce IL-17A in T cells plays a critical role in the pathogenesis of systemic lupus erythematosus (SLE). This research aimed to investigate the mechanisms regulating CREM alpha expression in SLE. Results: From the chromatin immunoprecipitation (ChIP) microarray data, we found a sharply increased H3 lysine 4 trimethylation (H3K4me3) amount at the CREM alpha promoter in SLE CD4+ T cells compared to controls. Then, by ChIP and real-time PCR, we confirmed this result. Moreover, H3K4me3 amount at the promoter was positively correlated with CREM alpha mRNA level in SLE CD4+ T cells. In addition, a striking increase was observed in SET domain containing 1 (Set1) enrichment, but no marked change in mixed-lineage leukemia 1 (MLL1) enrichment at the CREMa promoter in SLE CD4+ T cells. We also proved Set1 enrichment was positively correlated with both H3K4me3 amount at the CREMa promoter and CREMa mRNA level in SLE CD4+ T cells. Knocking down Set1 with siRNA in SLE CD4+ T cells decreased Set1 and H3K4me3 enrichments, and elevated the levels of DNMT3 alpha and DNA methylation, while the amounts of H3 acetylation (H3ac) and H4 acetylation (H4ac) didn't alter greatly at the CREMa promoter. All these changes inhibited the expression of CREM alpha, then augmented IL-2 and down-modulated IL-17A productions. Subsequently, we observed that DNA methyltransferase (DNMT) 3a enrichment at the CREM alpha promoter was down-regulated significantly in SLE CD4+ T cells, and H3K4me3 amount was negatively correlated with both DNA methylation level and DNMT3a enrichment at the CREM alpha promoter in SLE CD4+ T cells. Conclusions: In SLE CD4+ T cells, increased Set1 enrichment up-regulates H3K4me3 amount at the CREM alpha promoter, which antagonizes DNMT3a and suppresses DNA methylation within this region. All these factors induce CREM alpha overexpression, consequently result in IL-2 under-expression and IL-17A overproduction, and contribute to SLE at last. Our findings provide a novel approach in SLE treatment.