Inhibited expression of hematopoietic progenitor kinase 1 associated with loss of jumonji domain containing 3 promoter binding contributes to autoimmunity in systemic lupus erythematosus
Inhibited expression of hematopoietic progenitor kinase 1 associated with loss of jumonji domain containing 3 promoter binding contributes to autoimmunity in systemic lupus erythematosus
复制标题
造血祖细胞激酶 1 的抑制表达与含有 3 启动子结合的 jumonji 结构域丢失相关，有助于系统性红斑狼疮的自身免疫
DOI：
10.1016/j.jaut.2011.09.006
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发表时间：
2011-11-01
影响因子：
12.8
通讯作者：
Lu, Qianjin
中科院分区：
文献类型：
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作者：
Zhang, Qing;Long, Hai;Lu, Qianjin
系统性红斑狼疮(SLE)是一种以T细胞过度活化和B细胞过度刺激为特征的自身免疫性疾病。造血祖细胞激酶1(HPK1，又称MAP4K1)负向调节T细胞介导的免疫反应。然而，HPK1在SLE中的作用和调节HPK1表达的机制仍然知之甚少。利用染色质免疫沉淀(CHIP)芯片数据，我们发现与对照组相比，SLE CD4+T细胞HPK1启动子上组蛋白H3赖氨酸27三甲基化(H3K27me3)显著增加，并通过CHIP和实时定量PCR实验证实了这一观察结果。我们进一步发现，在SLE患者的CD4+T细胞中，HPK1的mRNA和蛋白水平显著降低，并且这种下降不是由暴露于标准的SLE药物引起的。下调健康CD4+T细胞中HPK1的表达可显著促进T细胞的增殖和产生干扰素-γ和免疫球蛋白G。与这些发现一致的是，在SLE CD4+T细胞中过表达HPK1导致T细胞反应性显著降低。此外，我们观察到，与健康对照组相比，SLE CD4+T细胞HPK1启动子区域的Jumonji结构域包含3(JMJD3)结合显著减少，但ZEST同源2增强子(EZH2)结合没有明显变化。在健康的CD4+T细胞中，JMJD3的siRNA敲除导致JMJD3结合减少，并增加H3K27me3在HPK1启动子区域的聚集，从而抑制HPK1的表达。相应地，在SLE CD4+T细胞中，质粒诱导的JMJD3过表达导致JMJD3结合增加，H3K27me3浓集减少，HPK1表达上调。我们的结果首次表明，抑制SLE CD4+T细胞HPK1的表达与JMJD3结合的丧失和H3K27me3在HPK1启动子上的聚集增加有关，这是导致SLE T细胞过度激活和B细胞过度刺激的原因之一。这些发现表明，HPK1可能成为有效治疗SLE的新靶点。(C)2011爱思唯尔有限公司。保留所有权利。
Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by T cell overactivation and B cell hyper-stimulation. Hematopoietic progenitor kinase 1 (HPK1, also called MAP4K1) negatively regulates T cell-mediated immune responses. However, the role of HPK1 and the mechanisms that regulate HPK1 expression in SLE remain poorly understood. Using chromatin immunoprecipitation (ChIP) microarray data, we identified markedly increased histone H3 lysine 27 trimethylation (H3K27me3) enrichment at the HPK1 promoter of SLE CD4+ T cells relative to controls, and confirmed this observation using ChIP and real-time PCR experiments. We further found that HPK1 mRNA and protein levels were significantly decreased in CD4+ T cells of patients with SLE, and that this decrease was not caused by exposure to standard SLE medications. Down-regulating HPK1 in healthy CD4+ T cells significantly accelerated T cell proliferation and production of IFN gamma and IgG. Consistent with these findings, overexpressing HPK1 in SLE CD4+ T cells caused a significant decrease in T cell reactivity. In addition, we observed a striking decrease in jumonji domain containing 3 (JMJD3) binding, but no marked change in enhancer of zeste homolog 2 (EZH2) binding, at the HPK1 promoter region in SLE CD4+ T cells compared to healthy controls. SiRNA knock down of JMJD3 in healthy CD4+ T cells led to decreased JMJD3 binding and increased H3K27me3 enrichment at the HPK1 promoter region, thus inhibiting the expression of HPK1. Concordantly, plasmid-induced overexpression of JMJD3 in SLE CD4+ T cells led to increased JMJD3 binding, decreased H3K27me3 enrichment, and up-regulated HPK1 expression. Our results show for the first time that inhibited HPK1 expression in SLE CD4+ T cells is associated with loss of JMJD3 binding and increased H3K27me3 enrichment at the HPK1 promoter, contributing to T cell overactivation and B cell overstimulation in SLE. These findings suggest that HPK1 may serve as a novel target for effective SLE therapy. (C) 2011 Elsevier Ltd. All rights reserved.