Epigenetics and SLE: RFX1 downregulation causes CD11a and CD70 overexpression by altering epigenetic modifications in lupus CD4+ T cells
Epigenetics and SLE: RFX1 downregulation causes CD11a and CD70 overexpression by altering epigenetic modifications in lupus CD4+ T cells
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DOI：
10.1016/j.jaut.2010.02.002
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发表时间：
2010-08-01
影响因子：
12.8
通讯作者：
Lu, Qianjin
中科院分区：
文献类型：
--
作者：
Zhao, Ming;Sun, Yimin;Lu, Qianjin
CD11a 和 CD70 调节区的 DNA 去甲基化和组蛋白高乙酰化有助于系统性红斑狼疮 (SLE) 患者 CD4(+) T 细胞发生自身反应性和自身抗体过度刺激。然而，引起这些变化的机制仍然很大程度上未知。我们报道SLE CD4(+) T细胞中转录因子RFX1的表达和活性降低。我们证明RFX1通过将共阻遏物DNMT1和HDAC1招募到CD11a和CD70启动子来影响CD4+T细胞中的DNA甲基化和组蛋白乙酰化，从而抑制它们的表达。减少CD4+T细胞中的RFX1足以引起狼疮样T细胞和B细胞过度活跃，而过表达RFX1则抑制T细胞反应性。这些发现揭示了： RFX1 在调节 T 细胞表观遗传状态中发挥着至关重要的作用，并证明 SLE 中的自身免疫反应部分归因于 RFX1 下调。 (C) 2010 Elsevier Ltd. 保留所有权利。
DNA demethylation and histone hyperacetylation of CD11a and CD70 regulatory regions contribute to the development of autoreactivity and autoantibody overstimulation in CD4(+) T cells of patients with systemic lupus erythematosus (SLE). However, the mechanisms causing these changes remain largely unknown. We report that the expression and activity of the transcription factor RFX1 are decreased in SLE CD4(+) T cells. We demonstrate that RFX1 affects DNA methylation and histone acetylation in CD4(+) T cells by recruiting the co-repressors DNMT1 and HDAC1 to the CD11a and CD70 promoters, and thereby represses their expression. Reducing RFX1 in CD4(+) T cells is sufficient to cause lupus-like T and B cell hyperactivity, whereas overexpressing RFX1 suppresses T cell reactivity. These findings reveal a. crucial role for RFX1 in regulating the epigenetic status of T cells, and demonstrate that autoimmune responses in SLE are due in part to RFX1 downregulation. (C) 2010 Elsevier Ltd. All rights reserved.