Decreased SUV39H1 at the promoter region leads to increased CREMα and accelerates autoimmune response in CD4(+) T cells from patients with systemic lupus erythematosus.
Decreased SUV39H1 at the promoter region leads to increased CREMα and accelerates autoimmune response in CD4(+) T cells from patients with systemic lupus erythematosus.
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启动子区域 SUV39H1 减少导致 CREMα 增加，并加速系统性红斑狼疮患者 CD4 T 细胞的自身免疫反应
DOI：
10.1186/s13148-022-01411-7
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发表时间：
2022-12-20
影响因子：
5.7
通讯作者：
中科院分区：
文献类型：
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作者：
系统性红斑狼疮（SLE）患者外周血T细胞中cAMP反应元件调节因子α（CREMα）的过度表达可抑制IL-2的产生，增加IL-17 A的表达。这些最终促进SLE的进展。本研究旨在观察CREMα在SLE CD 4 + T细胞中的表达，探讨CREMα在SLE CD 4 + T细胞中的调控机制。SLE患者外周血CD 4 + T细胞CREMα mRNA高表达。SLE CD 4 + T细胞CREMα启动子区组蛋白H3赖氨酸9三甲基化（H3 K9 me 3）和变异抑制因子3-9同源物1（suppressor of variation 3-9 homolog 1，SUV 39 H1）水平明显降低。在正常CD 4 + T细胞中下调SUV 39 H1可升高CREMα启动子区的CREMα、IL-17 A和组蛋白H3赖氨酸4三甲基化（H3 K4 me 3）水平，并降低CREM α启动子区的IL-2、H3 K9 me 3、DNA甲基化和DNA甲基转移酶3a（DNMT 3a）富集，而CREMα启动子区的SET结构域1（Set 1）无明显变化。上调SLE CD 4 + T细胞中的SUV 39 H1具有相反的效果。SLE患者CD 4 + T细胞CREMα启动子区DNA甲基化水平和DNMT 3a水平明显降低，H3 K4 me 3富集明显增加。Set 1在CREMα启动子区的结合显著增强，在SLE CD 4 + T细胞中敲低Set 1可减轻H3 K4 me 3在该区域的富集，抑制CREMα和IL-17 A的产生，并促进IL-2、CREMα启动子DNA甲基化和DNMT 3a的水平。而转染后H3 K9 me 3和SUV 39 H1在该区域的表达量无明显变化。SLE患者CD 4 + T细胞CREMα启动子区SUV 39 H1的减少导致该区域H3 K9 me 3的低表达。同时，SLE CD 4 + T细胞CREMα启动子上的Set 1结合上调。结果，DNMT 3a和DNA甲基化水平减轻，H3 K4 me 3结合增加。所有这些都导致CREMα的过度产生。因此，IL-2的分泌下调，IL-17 A的浓度上调，最终促进SLE。
Overproduction of cAMP-responsive element modulator α (CREMα) in total T cells from patients with systemic lupus erythematosus (SLE) can inhibit IL-2 and increase IL-17A. These ultimately promote progression of SLE. This study aims to investigate the expression of CREMα in SLE CD4+ T cells and find out the mechanisms for the regulation of CREMα in SLE CD4+ T cells. CREMα mRNA was overexpressed in CD4+ T cells from SLE patients. The levels of histone H3 lysine 9 trimethylation (H3K9me3) and suppressor of variation 3–9 homolog 1 (SUV39H1) at the CREMα promoter of SLE CD4+ T cells were markedly decreased. Down-regulating SUV39H1 in normal CD4+ T cells elevated the levels of CREMα, IL-17A, and histone H3 lysine 4 trimethylation (H3K4me3) in the CREMα promoter region, and lowered IL-2, H3K9me3, DNA methylation, and DNA methyltransferase 3a (DNMT3a) enrichments within the CREMα promoter, while no sharp change in SET domain containing 1 (Set1) at the CREMα promoter. Up-regulating SUV39H1 in SLE CD4+ T cells had the opposite effects. The DNA methylation and DNMT3a levels were obviously reduced, and H3K4me3 enrichment was greatly increased at the CREMα promoter of CD4+ T cells from SLE patients. The Set1 binding in the CREMα promoter region upgraded significantly, and knocking down Set1 in SLE CD4+ T cells alleviated the H3K4me3 enrichment within this region, suppressed CREMα and IL-17A productions, and promoted the levels of IL-2, CREMα promoter DNA methylation, and DNMT3a. But there were no obviously alterations in H3K9me3 and SUV39H1 amounts in the region after transfection. Decreased SUV39H1 in the CREMα promoter region of CD4+ T cells from SLE patients contributes to under-expression of H3K9me3 at this region. In the meantime, the Set1 binding at the CREMα promoter of SLE CD4+ T cells is up-regulated. As a result, DNMT3a and DNA methylation levels alleviate, and H3K4me3 binding increases. All these lead to overproduction of CREMα. Thus, the secretion of IL-2 down-regulates and the concentration of IL-17A up-regulates, ultimately promoting SLE.
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影响因子：
--
作者：
Li, Yaping;Zhao, Ming;Lu, Qianjin
通讯作者：
Lu, Qianjin
影响因子：
12.8
作者：
Hewagama A;Richardson B
通讯作者：
Richardson B
影响因子：
30.5
作者：
Doreau, Agnes;Belot, Alexandre;Bonnefoy-Berard, Nathalie
通讯作者：
Bonnefoy-Berard, Nathalie
影响因子：
13.6
作者：
Katsiari, CG;Tsokos, GC
通讯作者：
Tsokos, GC
影响因子：
3.3
作者：
Jing, Jia;Li, Fenfen;Shi, Hang
通讯作者：
Shi, Hang