DNA甲基化在肿瘤发生中的重要作用已被大量实验证实。我们前期在子宫内膜癌中筛选出了两个呈高甲基化的抑癌基因- - -3OST2和SOCS3。DNA甲基化和组蛋白修饰往往相互作用共同调控基因表达。最新研究发现，UHRF1可双重识别甲基化的DNA和甲基化的H3K9，被认为是DNA甲基化和组蛋白修饰交叉对话中少数最关键的分子之一。我们的预实验结果表明，UHRF1可结合于3OST2和SOCS3启动子调控其表达，同时启动子区还结合有不同甲基化形式的H3R8。本项目拟在此基础上：1.明确UHRF1可与哪些组蛋白修饰酶形成复合体；2. 探讨UHRF1复合体介导的表观遗传网络对子宫内膜癌关键甲基化靶基因的调控机制；3. 敲除该调控网络中的关键基因，观察其对子宫内膜癌细胞浸润、转移的影响。本研究将对解读DNA甲基化和组蛋白修饰之间的相互作用以及设计特异的表观遗传药物具有重要的意义。

A great number of studies have proved that DNA methylation plays an important role in tumorigenesis. 3OST2 and SOCS3, as two tumor suppressor genes highly methylated in endometrial carcinoma, were selected in our early study. DNA methylation and histone modification usually interact to regulate gene expression. A recent research has found that UHRF1 can recognize both methylated DNA and methylated H3K9 and links them, thus, it is considered as one of the few most critical molecules in crosstalk between DNA methylation and histone modifications. Our pre-experiment has demonstrated that UHRF1 can bind to promoter of 3OST2 and SOCS3 to regulate their expression, and simultaneously, there is H3R8 in different methylation forms binding to the promoter region. Based on the fact above, our project is planned to: i. Clear which histone modification enzyme can bond with UHRF1 to form a complex; ii. Explore the regulation of target methylated genes by UHRF1-mediated epigenetic network in endometrial carcinoma; iii. Knockdown the key genes of this regulatory network and observe the influence on invasion and metastasis of endometrial carcinoma cells. This study will have great potential significance in interpreting the interaction between DNA methylation and histone modifications and the design of specific epigenetic drugs.

DNA甲基化和组蛋白修饰在肿瘤的发生发展中都起着重要作用，研究发现两者在基因表达调控通路中并非孤立存在，而是存在着紧密的联系。UHRF1可双重识别甲基化的DNA和甲基化的H3K9，被认为是DNA甲基化和组蛋白修饰交叉对话中少数最关键的分子之一。我们检测了多个抑癌基因在一系列子宫内膜病变(包括正常子宫内膜、单纯性增生、复杂性增生、不典型增生和I型子宫内膜癌)中的甲基化情况，筛选出了两个在子宫内膜癌中具有早期诊断意义的抑癌基因---3OST2和SCOS3；并发现UHRF1在子宫内膜样腺癌细胞胞核中呈特异性高表达，并能富集于3OST2和SCOS3基因启动子区，调控其基因表达。我们进一步检测了子宫内膜样腺癌中甲基化的3OST2和SCOS3基因启动子区H3R8的富集情况，结果发现除了UHRF1外，启动子区还富集有单甲基化(me1)和对称性双甲基化(me2s)的H3R8，而未检测到非对称性双甲基化(me2a)的H3R8。进一步研究发现，UHRF1可以与组蛋白精氨酸甲基化酶PRMT5形成复合体，并能通过ER信号通路调控子宫内膜样腺癌的发生发展。基因敲除掉该复合体中的关键基因PRMT5后，可抑制ER的表达，并显著抑制子宫内膜癌细胞的迁移能力。本研究对提供肝癌早期诊断标志物、解读DNA甲基化和组蛋白甲基化之间的相互作用具有重要的指导意义，为设计子宫内膜样腺癌表观遗传药物提供了靶点。