Tumor Suppressor Menin Represses Paired Box Gene 2 Expression via Wilms Tumor Suppressor Protein-Polycomb Group Complex*
Tumor Suppressor Menin Represses Paired Box Gene 2 Expression via Wilms Tumor Suppressor Protein-Polycomb Group Complex*
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DOI：
10.1074/jbc.m110.197830
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发表时间：
2011-03
期刊：
影响因子：
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通讯作者：
Bin Xu;De-quan Zeng;Yuan Wu;Rong Zheng;L. Gu;Xiao Lin;X. Hua;G. Jin
中科院分区：
文献类型：
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作者：
Bin Xu;De-quan Zeng;Yuan Wu;Rong Zheng;L. Gu;Xiao Lin;X. Hua;G. Jin
肿瘤抑制因子menin是MEN 1基因的产物，在控制组蛋白3赖氨酸4三甲基化（H3 K4 me 3）和基因转录中起关键作用，其可以调节增殖、凋亡和分化。然而，关于menin是否通过调节Polycomb组（PcG）蛋白复合物/H3 K27 me 3来控制基因表达以及细胞增殖和存活知之甚少。在这里，我们表明，menin特异性抑制转录因子配对盒基因2（Pax 2）通过PcG介导的H3 K27 me 3和Wilms肿瘤抑制蛋白（WT 1），锌指结构域的DNA结合蛋白。Menin不直接与Pax 2位点结合，而是上调WT 1表达。WT 1通过PcG依赖性H3 K27 me 3将PcG复合物募集到Pax 2启动子并抑制Pax 2的表达。此外，WT 1还与DNA甲基转移酶1（DNMT 1）相互作用，并将DNMT 1募集到Pax 2启动子，导致Pax 2启动子中CpG的超甲基化。总之，这些研究揭示了一种新的表观遗传机制，menin通过WT 1调节H3 K27 me 3和启动子DNA甲基化，并表明WT 1蛋白在调节menin/PcG轴，H3 K27甲基化和DNA甲基化的功能中起着重要的，但以前未被认识到的作用，导致基因转录的抑制。
Tumor suppressor menin, the product of the MEN1 gene, plays a key role in controlling histone 3 lysine 4 trimethylation (H3K4me3) and gene transcription, which can regulate proliferation, apoptosis, and differentiation. However, little is known as to whether menin controls gene expression and cell proliferation and survival via regulating Polycomb group (PcG) protein complex/H3K27me3. Here we show that menin specifically represses transcription factor Paired box gene 2 (Pax2) through PcG-mediated H3K27me3 and Wilms tumor suppressor protein (WT1), a zinc finger domain-containing DNA-binding protein. Menin does not directly bind to the Pax2 locus, instead, it up-regulates WT1 expression. WT1 recruits PcG complex to the Pax2 promoter and represses expression of Pax2 through PcG-dependent H3K27me3. Moreover, WT1 also interacts with DNA methyltransferase 1 (DNMT1), and recruits DNMT1 to the Pax2 promoter, resulting in hypermethylation of CpG in the Pax2 promoter. Together, these studies have uncovered a novel epigenetic mechanism whereby menin regulates H3K27me3 and promoter DNA methylation via WT1 and suggest that WT1 protein plays an important, yet previously unappreciated role in regulating the function of the menin/PcG axis, H3K27 methylation, and DNA methylation, resulting in repression of gene transcription.