组蛋白变异体在上皮间质转化过程中的作用以及相关组蛋白变异体密码的研究

项目名称： 组蛋白变异体在上皮间质转化过程中的作用以及相关组蛋白变异体密码的研究

项目编号： No.91219102

项目类型： 重大研究计划

立项/批准年度： 2013

项目学科： 遗传学与生物信息学、细胞生物学

项目作者： 石磊

作者单位： 天津医科大学

项目金额： 100万元

中文摘要： 上皮细胞间质转化(EMT)，作为一种典型的由表观遗传重编程机制决定的细胞可塑性现象，在肿瘤恶性转化过程中起着重要作用。与组蛋白修饰类似，组蛋白变异体在染色质结构维持和基因表达中也扮演着重要角色。但是组蛋白变异体是否在EMT重编程中起作用，尚且无人知晓。通过生物信息学分析我们发现组蛋白变异体mH2A2表达与乳腺癌的分化程度和转移能力呈负相关；初步研究表明，乳腺癌细胞中mH2A2维持了上皮标志物且抑制了间质标志物的表达。同时我们发现组蛋白变异体H2A.Z也调节着EMT相关分子的表达。今后，我们将在细胞和动物水平进一步探索二者在EMT中的作用。基于二者的表达在乳腺癌中呈负相关，且共同调节EMT相关分子Twist的表达，我们猜想它们很可能共同决定着EMT相关的组蛋白变异体密码，这一密码的破解将有助于我们从表观遗传学的角度更好的理解乳腺癌的EMT过程和分子机制，并为其治疗提供理论基础。

中文关键词： 乳腺癌；组蛋白变异体；组蛋白伴侣分子；上皮间质转化；

英文摘要： Epithelial-to-mesenchymal transition (EMT), which has been considered as an extreme example of cell plasticity, is important for malignant progression. Emerging evidence suggests widespread epigenetic reprogramming occur during malignant transformation. Like histone modifications, which are intensively investigated in epigenetic regulation, histone variants have a role of importance in chromatin structure maintenance and gene expression. But whether histone variants contribute to EMT related epigenetic reprogramming is still not known. Taking advantage of the oncomine cancer database, we found that histone H2A variant macroH2A2 (mH2A2), but not mH2A1, is profoundly associated with breast cancer differentiation, metastasis and patient survival. In addition, the expression level of mH2A2 negatively correlates with the invasive ability of breast cancer cells. mH2A2 depletion in MCF-7 cells promotes Twist and N-cadherin expression and down-regulates E-cadherin expression, while gain of function of mH2A2 in MDA-MB-231-cells results in decreased expression of Twist and N-cadherin and increased E-cadherin level. Twist has been reported as a master controller of EMT in breast cancer. N-cadherin and E-cadherin represent the mesenchymal and Epithelial marker, respectively. These results indicated that mH2A2 might be a nov

英文关键词： breast cancer；histone variant；histone chaperone；EMT；