EZH2 Modulates the DNA Methylome and Controls T Cell Adhesion Through Junctional Adhesion Molecule A in Lupus Patients.
EZH2 Modulates the DNA Methylome and Controls T Cell Adhesion Through Junctional Adhesion Molecule A in Lupus Patients.
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DOI：
10.1002/art.40338
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发表时间：
2018-01
期刊：
影响因子：
--
通讯作者：
Sawalha AH
中科院分区：
文献类型：
--
作者：
Tsou PS;Coit P;Kilian NC;Sawalha AH
EZH 2是介导H3 K27三甲基化和调节DNA甲基化的表观遗传调节因子。本研究的目的是描述EZH 2在狼疮发病机制中在CD 4 + T细胞中的作用。在从狼疮患者和健康对照分离的CD 4 + T细胞中测定EZH 2表达水平。使用全基因组DNA甲基化方法评估EZH 2过表达在CD 4 + T细胞中的表观遗传效应。通过qPCR评估基因表达和miRNA，同时通过蛋白质印迹法检查蛋白质表达。使用细胞粘附试验来评估CD 4 + T细胞与人微血管内皮细胞的粘附。与健康对照组相比，狼疮患者CD 4 + T细胞中EZH 2和H3 K27 me 3水平升高。miR-26 a和miR-101下调EZH 2，并且在狼疮CD 4 + T细胞中减少。在CD 4 + T细胞中过表达EZH 2导致显著的DNA甲基化变化。当EZH 2过表达时，参与白细胞粘附和迁移的基因，包括编码JAM-A的F11 R，在CD 4 + T细胞中变得低甲基化。EZH 2的过表达导致JAM-A表达和CD 4 + T细胞粘附增加。EZH 2转染的CD 4 + T细胞与针对JAM-A的中和抗体的预孵育显著钝化细胞粘附。类似地，与健康对照组的T细胞相比，狼疮患者的CD 4 + T细胞过表达JAM-A，并显著更多地粘附于内皮细胞。阻断JAM-A或EZH 2显著降低狼疮CD 4 + T细胞的内皮细胞粘附。我们确定了EZH 2在由表观遗传重塑和JAM-A上调介导的T细胞粘附中的新作用。阻断EZH 2或JAM-A可能通过减少T细胞粘附、迁移和外渗而具有治疗狼疮的潜力。
EZH2 is an epigenetic regulator that mediates H3K27 trimethylation and modulates DNA methylation. The aim of this study is to characterize the role of EZH2 in CD4+ T cells upon lupus pathogenesis. EZH2 expression levels were determined in CD4+ T cells isolated from lupus patients and healthy controls. The epigenetic effects of EZH2 overexpression in CD4+ T cells were evaluated using a genome-wide DNA methylation approach. Gene expression and miRNAs were assessed by qPCR while protein expression was examined by Western blotting. A cell adhesion assay was used to assess adhesion of CD4+ T cells to human microvascular endothelial cells. EZH2 and H3K27me3 levels were increased in CD4+ T cells in lupus compared to healthy controls. MiR-26a and miR-101 downregulated EZH2, and were reduced in lupus CD4+ T cells. Overexpressing EZH2 in CD4+ T cells resulted in significant DNA methylation changes. Genes involved in leukocyte adhesion and migration, including F11R encoding JAM-A, become hypomethylated in CD4+ T cells when EZH2 is overexpressed. Overexpression of EZH2 resulted in increased JAM-A expression and CD4+ T cell adhesion. Pre-incubation of EZH2-transfected CD4+ T cells with neutralizing antibodies against JAM-A significantly blunted cell adhesion. Similarly, CD4+ T cells from lupus patients overexpressed JAM-A and adhered significantly more to endothelial cells compared to T cells from healthy controls. Blocking JAM-A or EZH2 significantly reduced endothelial cell adhesion of lupus CD4+ T cells. We identified a novel role for EZH2 in T cell adhesion mediated by epigenetic remodeling and upregulation of JAM-A. Blocking EZH2 or JAM-A might have a therapeutic potential in lupus by reducing T cell adhesion, migration, and extravasation.
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影响因子：
30.5
作者：
Ostermann, G;Weber, KSC;Weber, C
通讯作者：
Weber, C
影响因子：
3.7
作者：
Kanduri, Meena;Sander, Birgitta;Rosenquist, Richard
通讯作者：
Rosenquist, Richard
影响因子：
--
作者：
RICHARDSON, B;SCHEINBART, L;JOHNSON, M
通讯作者：
JOHNSON, M
影响因子：
4.4
作者：
Li, Yansong;Harada, Tatsuhiro;Tsokos, George C.
通讯作者：
Tsokos, George C.
DOI：
10.1084/jem.190.9.1351
发表时间：
1999-11-01
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Del Maschio A;De Luigi A;Martin-Padura I;Brockhaus M;Bartfai T;Fruscella P;Adorini L;Martino G;Furlan R;De Simoni MG;Dejana E
通讯作者：
Dejana E