ETV2-TET1/TET2 Complexes Induce Endothelial Cell-Specific Robo4 Expression via Promoter Demethylation.
ETV2-TET1/TET2 Complexes Induce Endothelial Cell-Specific Robo4 Expression via Promoter Demethylation.
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DOI：
10.1038/s41598-018-23937-8
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发表时间：
2018-04-04
影响因子：
4.6
通讯作者：
Okada Y
中科院分区：
文献类型：
--
作者：
Tanaka T;Izawa K;Maniwa Y;Okamura M;Okada A;Yamaguchi T;Shirakura K;Maekawa N;Matsui H;Ishimoto K;Hino N;Nakagawa O;Aird WC;Mizuguchi H;Kawabata K;Doi T;Okada Y
虽然已经鉴定了调节内皮细胞（EC）特异性基因表达的转录因子，但尚不清楚这些因子如何诱导EC特异性。我们先前报道了近端启动子的DNA低甲基化导致Roundabout 4（Robo 4）的EC特异性表达。然而，建立EC特异性Robo 4启动子低甲基化的机制仍然未知。在这项研究中，我们证明了高甲基化的Robo 4近端启动子是去甲基化的人iPS细胞分化成内皮细胞。报告分析表明，ETV 2，ETS家族的转录因子，绑定到近端启动子和激活Robo 4表达的ETS基序。免疫沉淀显示ETV 2和甲基胞嘧啶转化酶TET 1和TET 2之间的直接相互作用。ETV 2-TET 1/TET 2复合物的腺病毒表达使Robo 4启动子去甲基化并诱导Robo 4在非EC中表达。总之，我们提出了一种新的EC特异性基因表达调节模型，该模型通过内皮分化期间ETV 2-TET 1/TET 2复合物诱导的启动子去甲基化来实现。
Although transcription factors regulating endothelial cell (EC)-specific gene expression have been identified, it is not known how those factors induce EC-specificity. We previously reported that DNA hypomethylation of the proximal promoter elicits EC-specific expression of Roundabout4 (Robo4). However, the mechanisms establishing EC-specific hypomethylation of the Robo4 promoter remain unknown. In this study, we demonstrated that the hypermethylated Robo4 proximal promoter is demethylated as human iPS cells differentiate into endothelial cells. Reporter assays demonstrated that ETV2, an ETS family transcription factor, bound to ETS motifs in the proximal promoter and activated Robo4 expression. Immunoprecipitation demonstrated direct interaction between ETV2 and methylcytosine-converting enzymes TET1 and TET2. Adenoviral expression of ETV2-TET1/TET2 complexes demethylated the Robo4 promoter and induced Robo4 expression in non-ECs. In summary, we propose a novel regulatory model of EC-specific gene expression via promoter demethylation induced by ETV2-TET1/TET2 complexes during endothelial differentiation.
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