Atrx 基因失活促进脑胶质瘤形成的表观遗传学机制研究

项目名称： Atrx 基因失活促进脑胶质瘤形成的表观遗传学机制研究

项目编号： No.81472344

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 张灵

作者单位： 吉林大学

项目金额： 68万元

中文摘要： 胶质瘤细胞依赖表观遗传途径维持异常更新，抑制细胞正常分化，成为恶性胶质瘤发病机制关键环节之一。利用表观遗传学机制干预，恢复肿瘤细胞表观遗传修饰正常状态，可为恶性胶质瘤治疗开辟新途径。在前期工作中，我们利用三种鼠源性胶质瘤始动细胞（GIC）对靶向243种染色质调控子shRNA表观遗传学文库逐一筛查，发现下调Atrx基因表达，能够明显促进小鼠GIC增殖，抑制其分化，故推测Atrx是潜在脑胶质瘤抑癌基因。在本项目中，我们拟利用RNA干扰技术下调Atrx基因表达，观察在分化条件下，其对小鼠GIC及神经干细胞(NSC)的增殖、分化以及脑胶质瘤发生产生的影响。并以此为基础，利用细胞免疫染色，ChIP 测序及RNA测序等技术，从分子、细胞及动物模型水平，揭示Atrx基因缺失促进脑胶质瘤形成的表观遗传学分子机制。为深化对脑胶质瘤发病机理的认识，推进针对脑胶质瘤表观遗传学新疗法的开发提供理论基础与实验数据。

中文关键词： 表观遗传；C15_脑；中枢神经系统肿瘤；X连锁α地中海贫血/智能发育迟滞蛋白；RNA干涉；分化

英文摘要： Given that one key event in glioma pathogenesis is the corruption of cell differentiation programs, it stands to reason that glioma cells may depend on distinct epigenetic pathways to sustain aberrant self-renewal against differentiation, and therefore be uniquely sensitive to certain perturbations of epigenetic structures. So using the epigenetic mechanisms to intervene and restore to their normal state by epigenetic therapy, makes such initiatives promising and therapeutically relevant. Previously, we used a customized shRNA library targeting 243 known chromatin regulators and performed the primary screen using one-by-one approach in three independent derived mouse glioma tumor-initiating lines. During the screening, we found that knockdown of Atrx by shRNAs promotes glioma initiating cells self-renewal and surpress the differentiation, indicating that Atrx is a potential glioma tumor suppressor. In this project, we are going to use Atrx shRNA to downregulate the Atrx expression in mouse glioma tumor-initiating cells and mouse neural stem cells, Analysis the effects of the differentiation and proliferation under the differentiation condition. Then we will perform RNA-seq and CHIP-sequencing to understand the epigenetics molecular mechanism of Atrx during glioma pathogenesis. This project will provide theoretical basis and experimental basis for the the invention of novel therapeutics informed by an enhanced understanding of its molecular pathogenesis.

英文关键词： epigenetics;gliomas;Atrx;RNA interference;Differentiation