Abstract
BackgroundUp-regulated cyclic adenosine 5'-monophosphate response element modulator α (CREMα) 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 CREMα expression in SLE.ResultsFrom the chromatin immunoprecipitation (ChIP) microarray data, we found a sharply increased H3 lysine 4 trimethylation (H3K4me3) amount at the CREMα 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 CREMα 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 CREMα promoter in SLE CD4+ T cells. We also proved Set1 enrichment was positively correlated with both H3K4me3 amount at the CREMα promoter and CREMα 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 DNMT3a and DNA methylation, while the amounts of H3 acetylation (H3ac) and H4 acetylation (H4ac) didn’t alter greatly at the CREMα promoter. All these changes inhibited the expression of CREMα, then augmented IL-2 and down-modulated IL-17A productions. Subsequently, we observed that DNA methyltransferase (DNMT) 3a enrichment at the CREMα 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 CREMα promoter in SLE CD4+ T cells.ConclusionsIn SLE CD4+ T cells, increased Set1 enrichment up-regulates H3K4me3 amount at the CREMα promoter, which antagonizes DNMT3a and suppresses DNA methylation within this region. All these factors induce CREMα 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s13148-016-0294-2) contains supplementary material, which is available to authorized users.
Highlights
Up-regulated cyclic adenosine 5'-monophosphate response element modulator α (CREMα) which can inhibit IL-2 and induce IL-17A in T cells plays a critical role in the pathogenesis of systemic lupus erythematosus (SLE)
H3 lysine trimethylation (H3K4me3) enrichment at the CREMα promoter was significantly increased in SLE CD4+ T cells (Fig. 2a, Additional file 1: Table S2), consistent with our chromatin immunoprecipitation (ChIP) microarray result
We further carried out real-time RT-PCR to examine CREMα mRNA level in CD4+ T cells from SLE patients, and documented that H3K4me3 enrichment at the promoter was positively correlated with CREMα mRNA level in SLE CD4+ T cells (Fig. 2b)
Summary
Up-regulated cyclic adenosine 5'-monophosphate response element modulator α (CREMα) which can inhibit IL-2 and induce IL-17A in T cells plays a critical role in the pathogenesis of systemic lupus erythematosus (SLE). As one of the most familiar histone modifications, H3K4me is always a focus of epigenetics It accumulates predominantly at the promoters and early transcribed regions of active genes, and is involved in transcription initiation, elongation and RNA processing by interacting with RNA polymerase II [12, 13]. It can recruit and/or stabilize chromatin-remodeling enzymes and transcriptional cofactors [14, 15]. Histone methyltransferases (HMTs) SET domain containing 1 (Set1) and mixed-lineage leukemia 1 (MLL1) can both catalyze trimethylation of H3K4 [18, 19]
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