Background/Purpose: In recent years, accumulating evidence has demonstrated that increased cAMP response element modulator α (CREMα) which contributes to IL-2 reduction and IL-17A overproduction in T cells plays an essential role in the pathogenesis of systemic lupus erythematosus (SLE). The aim of this study is to investigate what regulate CREMα expression in SLE.

Methods: CD4+ T cells were isolated from SLE patients and healthy controls. Histone H3 lysine 4 trimethylation (H3K4me3, a prevalent mark associated with transcription activation) enrichment at various gene promoters in CD4+ T cells from 5 SLE patients and 5 healthy controls was analyzed by chromatin immunoprecipitation (ChIP) microarray. Amounts of H3K4me3, Set1 and MLL1 (both are H3K4 methyltransferases) within the CREMα promoter were subsequently analyzed by ChIP and real-time PCR in CD4+ T cells from 15 SLE patients and 15 healthy controls. And CREMα mRNA levels were determined by real-time RT-PCR.

Results: In ChIP microarray data, we identified sharply increased H3K4me3 enrichment at the CREMα promoter of SLE CD4+ T cells relative to controls. Then by ChIP and real-time PCR experiments, we confirmed this result. Moreover, H3K4me3 enrichment at the promoter was positively correlated with CREMα mRNA levels in SLE CD4+ T cells. In addition, a striking increase was observed in Set1 binding, but no marked change in MLL1 binding at the CREMα promoter region in SLE CD4+ T cells compared to healthy controls. We also proved the levels of Set1 binding were positively correlated with H3K4me3 enrichment at the CREMα promoter, and positively correlated with CREMα mRNA levels. Knocking down Set1 with siRNA in SLE CD4+ T cells led to decreased Set1 binding and H3K4me3 enrichment at the CREMα promoter region, thus inhibiting the expression of CREMα.

Conclusion: Our findings suggest for the first time that increased Set1 binding up-regulates H3K4me3 enrichment at the CREMα promoter, which induces CREMα overexpression in SLE CD4+ T cells, and contributes to the development of SLE at last. These results can help elucidate the molecular pathogenesis of SLE, and provide a novel way and target for effective SLE therapy.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/overexpression-of-set1-at-the-promoter-contributes-to-camp-response-element-modulator-alpha-overexpression-in-systemic-lupus-erythematosus/