MLL促进肝癌的靶基因鉴定及其表观遗传学特性的研究

项目名称： MLL促进肝癌的靶基因鉴定及其表观遗传学特性的研究

项目编号： No.81472230

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： 李善花

作者单位： 厦门大学

项目金额： 75万元

中文摘要： MLL是诱发白血病的关键原癌基因，但在其他肿瘤中的生物学作用尚不清楚。我们发现，MLL参与menin促进的Yap1基因转录激活及肝癌发生，其机制可能依赖于H3K4等正性组蛋白甲基化修饰，但精确的调控机制及组蛋白修饰规律有待进一步深入阐明。本项目利用MLL基因组织特异性敲除等小鼠建立DEN诱导的原发性肝癌疾病模型，证实MLL促进肝癌恶性表型的关键生物学功能，评价病理学特点；从已获得的染色质组蛋白甲基化等组学数据的整合分析入手，利用ChIP等关键技术深入筛选和鉴定肝癌中受MLL调控的靶基因网络，明确MLL调控关键靶基因转录的优势组蛋白甲基化修饰规律、鉴定组蛋白甲基转移酶复合物组成；探讨以MLL调控的正性组蛋白甲基化修饰为靶点的小分子化合物在肝癌治疗中的潜在应用前景。这将有助于揭示正性组蛋白甲基化异常修饰促进肝癌发生的表观遗传学机制，为肝癌防治提供崭新的靶点。

中文关键词： MLL；肝癌；表观遗传

英文摘要： MLL is a critical oncogene on inducing Leukemia, but its biological functions in other tumors are still unclear. We have shown that MLL is involved in the activation of Yap1 transcription and the induction of hepatocellular carcinoma (HCC) promoted by menin, Its mechanism maybe depend on the H3K4 positive histone methylation, but the exact regulation mechanisms and histone modification patterns need to be further determined. This study utilizes HCC model induced by DEN in MLL gene tissue-specific knockout mice, in order to confirm that MLL promotes the key biological functions of the malignant phenotype in HCC, and evaluate its pathological characteristics. Based on the analysis of the chromatin histone methylation which has been obtained from data integration, using ChIP and other key technologies, the target genes network regulated by MLL will be screened and identified in HCC. The advantage of MLL on regulating histone methylation modification of target genes transcription and its partners of histone methyltransferase complex will be further clarified. We will also investigate the potential application prospect of the small molecular MLL target compounds on the treatment of HCC. This study will be helpful on revealing the epigenetic mechanism of the positive histone methylation modification on promoting hepatocarcinogenesis. It will provide a new therapeutic target on the treatment of HCC.

英文关键词： MLL;Hepatocellular carcinoma;Epigenetic