组蛋白甲基化与癌基因组突变相关性研究

项目名称： 组蛋白甲基化与癌基因组突变相关性研究

项目编号： No.81502437

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： 张亮生

作者单位： 同济大学

项目金额： 18.5万元

中文摘要： 突变是癌症发生的驱动力。DNA甲基化和组蛋白修饰等表观遗传因素对癌细胞命运的影响不可或缺。其中组蛋白甲基化尤其复杂，既抑制又激活基因的表达，还与染色质结构变异等相关。组蛋白甲基化由SET结构域蛋白催化，而SET结构域蛋白本身是重要的潜在药物靶点。.癌细胞突变在基因组上不是均匀分布的。某些癌症中的突变与组蛋白甲基化信号在基因组的上分布具有较强的相关性，例如黑色素瘤的基因组突变频率与H3K4me1分布相关性很高 （r=0.8）。这种相关性可能与SET基因的突变或表达量变化相关，即SET基因的变化可能影响体细胞突变。.因此，本项目拟利用已有的各种癌症全基因组数据与各种细胞或组织的组蛋白甲基化信号进行比较分析，识别与各种癌症相关性最强的组蛋白甲基化信号以及相应的SET基因变化，进而利用重要的组蛋白甲基化信号对癌症进行分型分析。本项目将为临床分型、诊断、表观干预治疗癌症提供强有力的理论和技术支撑。

中文关键词： 组蛋白甲基化；SET结构域基因；突变；癌基因组；相关性

英文摘要： DNA Mutations are the driving force behind cancer. DNA methylation, histone modifications and other epigenetic mechanisms are very important for cell destiny. Histone methylation is particularly complex, which cannot only repress gene expression but also activate gene expression, and is associated with the structure variation of chromosome. Histone methylation is catalyzed by the SET domain proteins, which are important potential therapeutic targets. .Mutations are not distributed evenly across a cancer cell’s genome. The strongly correlation of mutation and the distribution of histone methylation in genome has been found in some cancer. For example, melanoma mutations are highly correlated with the levels of H3K4me1 in melanocytes (r=0.8). This correlation may be associated with mutations or expression level changes of SET domain genes, which means that the change of SET domain genes may be associated with cancer mutational landscape. .To test the diverse correlation, we intend to compare with correlation mutation rates in cancer genomes and histone methylation signals of various cells or tissues. We plan to identify the most relevant histone methylation signals in various types of cancer, and discovery the SET domain genes regulating the signals. Then, we use the important histone methylation signal for cancer typing. This project intends to provide a strong theoretical support for clinical classification, epigenetic biomarker discovery and effective treatment of cancer through epigenetic intervention.

英文关键词： Histone methylation;SET domain gene;Mutation;Cancer genomic;Correlation