组蛋白去甲基化酶LSD1的抑制剂通过调节转录因子治疗MLL白血病的研究

项目名称： 组蛋白去甲基化酶LSD1的抑制剂通过调节转录因子治疗MLL白血病的研究

项目编号： No.81470340

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： 和夫红

作者单位： 中国科学院北京基因组研究所

项目金额： 75万元

中文摘要： 表观遗传药物如组蛋白修饰酶抑制剂是白血病治疗中有极大潜力的新型药物。然而相关的作用机理不清影响了这一类药物的发展和疗效提高。组蛋白去甲基化酶LSD1抑制剂能特异性升高组蛋白H3赖氨酸4的二甲基化（H3K4me2），通过未知的分子机制治疗MLL白血病。基于H3K4me2与关键转录因子（如PU.1）募集和转录活性的功能调节关系，我们将用前期已初步建立的LSD1抑制剂诱导MLL白血病细胞的分化模型，研究诱导后H3K4me2的基因组分布和转录组的关键改变，确定H3K4me2改变与PU.1的募集和转录活性的关联。进一步通过序列信息分析寻找其他关键转录因子，并用ChIP测序确定其与H3K4me2间的调节关系。最后，用基因敲低等实验验证LSD1抑制剂的功能效应依赖于转录因子，并确定对下游基因的转录调节。本研究将揭示LSD1抑制剂靶向关键转录因子治疗MLL白血病的机制，为开发更有效的表观遗传药物奠定基础。

中文关键词： MLL白血病；LSD1；H3K4me2；转录因子；组蛋白修饰酶抑制剂

英文摘要： Epigenetic drugs has great potential for new drugs in leukemia therapy, such as inhibitors of histone modification enzymes. However, the mechanism associated with epigenetic drugs in leukemia therapy is still unclear, which influences the improvement of the development and therapeutic efficacy for epigenetic drugs. Histone demethylase LSD1 inhibitors specifically upregulate histone H3 lysine 4 dimethylation (H3K4me2) and treat MLL leukemia using an unknown molecular mechanism. Based on the regulatory association of H3K4me2 with recruitment and transcriptional activity of key transcription factors (such as PU.1), we will apply our preliminarily established models of LSD1 inhibitors-induced MLL leukemia cell differentiation, to investigate critical changes in genome-wide distribution of H3K4me2 and transcriptome upon using LSD1 inhibitors. We will also explore the effect of H3K4me2 changes on the recruitment and transcriptional activity of PU.1. Then, we will further find other key transcription factors important in this process using sequence analysis of differential H3K4me2 enrichment regions, and confirm the regulatory relationship between these transcription factors and H3K4me2 using a ChIP-seq assay. Finally, we will perform functional experiments including gene knockdown functional assays, to validate that functional effects induced by LSD1 inhibitors depend on these key transcription factors, and determine transcriptional regulation of these LSD1 inhibitors and transcription factors on their downstream genes. These studies will reveal the mechanism by which LSD1 inhibitors treat MLL leukemia via targeting key transcriptional factors, and lay the foundation for developing more efficacious epigenetic drugs.

英文关键词： MLL Leukemia;LSD1;H3K4me2;Transcription Factor;Histone Modification Enzyme Inhibitor