Abstract: Objective Increased cAMP response element modulator α (CREMα) in T cells plays an essential role in the pathogenesis of systemic lupus erythematosus (SLE). The aim of this study was to investigate the mechanisms that elevates CREMα expression in SLE. Methods CD4+ T cells from 5 healthy volunteers and 5 SLE patients were isolated for analysis of histone H3 lysine 27 trimethylation (H3K27me3) enrichment in different gene promoters using chromatin immunoprecipitation (ChIP) microarray. The levels of H3K27me3, H3K27 demethylases Jumonji domain containing 3 (JMJD3) and ubiquitously transcribed X (UTX), and H3K27 methyltransferase enhancer of zeste homolog 2 (EZH2) within the CREMα promoter were subsequently tested by ChIP and real-time PCR in CD4+ T cells from 30 normal controls and 30 SLE patients; CREMα mRNA level was also determined by real-time RT-PCR. Results Analysis of ChIP microarray data identified that H3K27me3 enrichment at the CREMα promoter in CD4+ T cells from SLE patients was 0.23 times that of the normal control subjects. The results of ChIP and real-time PCR confirmed a marked decrease of H3K27me3 enrichment at the CREMα promoter in CD4+ T cells from SLE patients (P<0.001). The level of H3K27me3 at the promoter was negatively correlated with CREMα mRNA level in CD4+ T cells from SLE patients (P<0.001). In addition, a sharp increase was observed in JMJD3 binding at the CREMα promoter region in CD4+ T cells from SLE patients (P<0.001), and it was negatively correlated with H3K27me3 enrichment (P<0.001) and positively correlated with CREMα mRNA level (P<0.001). There were no significant changes in UTX (P=0.172) or EZH2 (P=0.281) binding at the CREMα promoter region in CD4+ T cells from SLE patients as compared to normal controls. Conclusion Increased JMJD3 binding down-regulates H3K27me3 enrichment at the CREMα promoter in CD4+ T cells of SLE patients to stimulate CREMα overexpression and result in the development of SLE.