The oncoprotein EVI1 and the DNA methyltransferase Dnmt3 co-operate in binding and de novo methylation of target DNA.
The oncoprotein EVI1 and the DNA methyltransferase Dnmt3 co-operate in binding and de novo methylation of target DNA.
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DOI：
10.1371/journal.pone.0020793
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Nucifora G
中科院分区：
文献类型：
--
作者：
Senyuk V;Premanand K;Xu P;Qian Z;Nucifora G
EVI1在小鼠胚胎发生过程中具有多效性功能，其靶向破坏通过严重影响几乎所有胚胎器官的发育而导致产前死亡。然而，其在成人组织中的功能仍不清楚。当表达不当时，EVI1 会成为与人类造血系统癌症和实体癌相关的最具侵袭性的癌基因之一。 EVI1转化正常细胞的机制尚不清楚，但我们最近发现，EVI1通过microRNA-124-3（miR-124-3）调控区域中CpG二核苷酸的不适当甲基化，间接上调自我更新和细胞周期基因，导致这个控制体细胞正常分化和细胞周期的小基因受到抑制。我们使用 miR-124-3 的调控区域作为读出系统来研究 EVI1 如何诱导 DNA 从头甲基化。在这里，我们展示了 EVI1 与 DNA 甲基转移酶 3a 和 3b (Dnmt3a/b) 发生物理相互作用，这是迄今为止在小鼠和人类中发现的唯一从头 DNA 甲基转移酶，并且它形成了一种具有酶活性的蛋白质复合物，可在体外诱导 DNA 从头甲基化。该蛋白复合物靶向并结合 miR-124-3 的精确区域，该区域对于 EVI1 抑制报告基因是必需的。基于我们的研究结果，我们提出，EVI1 与 Dnmt3a/b 合作，作为 DNA 从头甲基化的序列特异性介体来调节 DNA 甲基化，并且不适当的 EVI1 表达会通过不适当的 DNA 甲基化促进致癌。
EVI1 has pleiotropic functions during murine embryogenesis and its targeted disruption leads to prenatal death by severely affecting the development of virtually all embryonic organs. However, its functions in adult tissues are still unclear. When inappropriately expressed, EVI1 becomes one of the most aggressive oncogenes associated with human hematopoietic and solid cancers. The mechanisms by which EVI1 transforms normal cells are unknown, but we showed recently that EVI1 indirectly upregulates self-renewal and cell-cycling genes by inappropriate methylation of CpG dinucleotides in the regulatory regions of microRNA-124-3 (miR-124-3), leading to the repression of this small gene that controls normal differentiation and cell cycling of somatic cells. We used the regulatory regions of miR-124-3 as a read-out system to investigate how EVI1 induces de novo methylation of DNA. Here we show that EVI1 physically interacts with DNA methyltransferases 3a and 3b (Dnmt3a/b), which are the only de novo DNA methyltransferases identified to date in mouse and man, and that it forms an enzymatically active protein complex that induces de novo DNA methylation in vitro. This protein complex targets and binds to a precise region of miR-124-3 that is necessary for repression of a reporter gene by EVI1. Based on our findings, we propose that in cooperation with Dnmt3a/b EVI1 regulates the methylation of DNA as a sequence-specific mediator of de novo DNA methylation and that inappropriate EVI1 expression contributes to carcinogenesis through improper DNA methylation.
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