肝癌中印记基因IGF2转录激活的H3K4组蛋白甲基化修饰机制

项目名称： 肝癌中印记基因IGF2转录激活的H3K4组蛋白甲基化修饰机制

项目编号： No.81502444

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 郑启凡

作者单位： 厦门大学

项目金额： 18万元

中文摘要： IGF2是典型印记基因，但在肝癌中IGF2的表达并不遵循印记调控规律，其原因尚不清楚。我们发现，肝癌中MEN1基因的编码蛋白menin调控的H3K4组蛋白甲基化通过TP53依赖性方式激活印记状态的IGF2表达，是目前未被关注的印记调控开关之一。本研究拟从已获得的组学数据的整合性分析入手，利用MEN1、MLL等基因肝脏特异性敲除小鼠模型，采用ChIP、3C等技术，鉴定肝脏病生理过程中参与IGF2转录激活的组蛋白甲基转移酶复合物组成及其组蛋白共价修饰规律；分析组蛋白共价修饰对IGF2-H19基因印记调控区域染色体结构的影响；阐明TP53通路介导的印记调控区域DNA超甲基化在H3K4激活的IGF2印记释放中的关键作用；揭示menin/MLL复合物调控的H3K4组蛋白修饰与DNA甲基化、H3K27组蛋白甲基化等传统印记调控机制之间的关系。这将有助于从H3K4正性组蛋白修饰角度丰富印记基因调控理论。

中文关键词： MEN1基因；肝细胞癌；印记基因；组蛋白修饰

英文摘要： IGF2 is a typical imprinting gene, but it the reason why the expression of IGF2 is not regulated by the classical imprinting mechanism in hepatocellular carcinoma (HCC) is still unknown. We found that as the product of MEN1, menin promoted the expression of imprinted IGF2 via H3K4 trimethylation modification in TP53 dependent manner in HCC. The histone 3 lysine 4 trimethylation (H3K4me3) is one of switches not noticed which could regulate the imprinting status. In this research, we will initiate through integrated analysis of ChIP-on-chip and expression profile data, utilize the MEN1、MLL knockout or tissue specific knockout mouse models, make use of ChIP、3C and other technologies, to reveal the regulation law between menin/MLL histone methyl-transferase(HMT) complex and imprinting gene such as IGF2 in the process of liver pathophysiology, then identify the histone modification features and composition of HMT complex; analyse the chromosome structure of the imprinting regulation domain of IGF2-H19 affected by histone modification; illustrate the key role of TP53 pathway mediated DNA hypermethylation of imprinting regulation domain during H3K4 activated loss of impringting of IGF2, explain the H3K4me3, H3K27me3 modification and DNA methylation to traditional regulation machanism of imprinting. These results will help enrich the essential theory of gene imprinting regulation through positive histone modification of H3K4me3.

英文关键词： MEN1 gene;hepatocellular carcinoma;imprinting gene;histone modification