Department of Dermatology, Second Xiangya Hospital, Central South University, Hunan Key Laboratory of Medical Epigenomics, Hunan, PR China.
Lupus. 2011 Nov;20(13):1365-71. doi: 10.1177/0961203311413412. Epub 2011 Aug 24.
In systemic lupus erythematosus (SLE), T lymphocytes overexpress CD70 (TNFSF7 gene), leading to the synthesis of autoreactive IgGs. CD70 upregulation in SLE CD4(+) T cells is associated with hypomethylation of TNFSF7 promoter. In this study, we explored histone modifications in the TNFSF7 promoter region in SLE CD4(+) T cells, and characterized the effects of a DNA methyltransferase inhibitor (5-azaC) and a histone deacetylase inhibitor (TSA) on CD70 expression. We found that CD70 mRNA was significantly increased in active lupus CD4(+) T cells, and in control cells treated with 5-azaC, TSA, or both. Histone H3 acetylation and dimethylated H3 lysine 4 (H3K4me2) levels were significantly elevated in patients with lupus, and both factors correlated positively with disease activity. MeCP2 protein levels within the TNFSF7 promoter decreased in patients with active lupus. Treatment of CD4+ T cells with 5-azaC alone significantly raised H3K4 dimethyl levels at the TNFSF7 locus. TSA treatment significantly increased H3 and H4 acetylation levels, as well as levels of H3K4 dimethylation at the TNFSF7 locus. Treatment with 5-azaC plus TSA enhanced H3 acetylation levels. These findings indicate that aberrant histone modifications within the TNFSF7 promoter may contribute to the development of lupus by increasing CD70 expression in CD4(+) T cells.
在系统性红斑狼疮（SLE）中，T 淋巴细胞过度表达 CD70（TNFSF7 基因），导致自身反应性 IgG 的合成。SLE CD4(+) T 细胞中 CD70 的上调与 TNFSF7 启动子的低甲基化有关。在这项研究中，我们探讨了 SLE CD4(+) T 细胞中 TNFSF7 启动子区域的组蛋白修饰，并研究了 DNA 甲基转移酶抑制剂（5-azaC）和组蛋白去乙酰化酶抑制剂（TSA）对 CD70 表达的影响。我们发现，活性狼疮 CD4(+) T 细胞中 CD70 mRNA 显著增加，而在对照细胞中用 5-azaC、TSA 或两者处理后也显著增加。狼疮患者的组蛋白 H3 乙酰化和组蛋白 H3 赖氨酸 4 二甲基化（H3K4me2）水平显著升高，且这两个因素与疾病活动度呈正相关。狼疮患者的 TNFSF7 启动子内 MeCP2 蛋白水平降低。单独用 5-azaC 处理 CD4+T 细胞可显著提高 TNFSF7 基因座处的 H3K4 二甲基化水平。TSA 处理可显著增加 H3 和 H4 乙酰化水平，以及 H3K4 二甲基化水平。5-azaC 和 TSA 的联合处理可增强 H3 乙酰化水平。这些发现表明，TNFSF7 启动子内异常的组蛋白修饰可能通过增加 CD4(+) T 细胞中 CD70 的表达，导致狼疮的发生。
