Background/Purpose: In recent years, accumulating evidences have demonstrated that increased cAMP response element modulator α (CREMα) which can inhibit IL-2 and induce IL-17A in CD4⁺ T cells plays an essential role in the pathogenesis of systemic lupus erythematosus (SLE). However, the molecular mechanisms that result in CREMα over expression remain poorly understood. The aim of this study is to investigate the mechanisms that regulate CREMα expression in SLE.

Methods: CD4⁺ T cells were isolated from healthy controls and SLE patients. Histone H3 lysine 9 trimethylation (H3K9me3, a hallmark associated with transcription inhibition) enrichments at various gene promoters in CD4⁺ T cells from 5 healthy controls and 5 SLE patients were analyzed by chromatin immunoprecipitation (ChIP) microarray. Amounts of H3K9me3, H3K9 methyltransferases SUV39H1 and SUV39H2 within the CREMα promoter were subsequently assessed by ChIP and real-time PCR in CD4⁺ T cells from 15 healthy controls and 15 SLE patients. And CREMα mRNA levels were determined by real-time RT-PCR.

Results: From the ChIP microarray data, we identified sharply decreased H3K9me3 enrichment at the CREMα promoter of SLE CD4⁺ T cells compared to healthy controls. Then by ChIP and real-time PCR experiments, we confirmed this finding. In addition, H3K9me3 enrichment at the promoter was negatively correlated with CREMα mRNA level in SLE CD4⁺ T cells. Moreover, a markedly decrease was observed in SUV39H1 binding, but no significant change in SUV39H2 enrichment at the CREMα promoter region in SLE CD4⁺ T cells. We also proved SUV39H1 binding was positively correlated with H3K9me3 amount at the CREMα promoter, and negatively correlated with CREMα mRNA level in CD4⁺ T cells from SLE patients.

Conclusion: Our findings suggest for the first time that decreased SUV39H1 binding down-regulates H3K9me3 enrichment at the CREMα promoter, which induces CREMα overexpression in SLE CD4⁺ T cells, and results in the development of SLE at last.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/aberrant-h3k9me3-modification-in-promoter-region-up-regulates-camp-response-element-modulator-alpha-in-systemic-lupus-erythematosus/