组蛋白H4K20多甲基化基因调控及识别机制研究

Gene transcription in eukaryotic cells can be regulated by methylation of both histones and DNA. However, the mechanism underlying methylation of histone H4K20 and gene expression is not fully understood so far. Using human globin gene as a model, this project is going to dissect the correlation between histone H4K20me2/3 methylation triggered by Suv4-20h1/2 and epsilon-globin gene expression. The coupled DNA methylation and other epigenetic histone markers will be also studied. More importantly, this project is going to probe the novel histone H4K20me2/3 recognition motif and related characteristics, and further to decode the epigenetic codes mediated by H4K20me2/3 both in vitro and in vivo, thus revealing the new mechanism by which epsilon-globin is developmentally silenced. All these studies will help rationalize targeted therapy of sickle cell disease and beta-thalassemia patients through reactivating early-globin genes expression in adults.

真核基因的转录广泛受到组蛋白修饰和DNA甲基化的调节。然而，多年来关于组蛋白H4K20甲基化与基因表达调控关系的机制研究并不够深入。本项目拟应用人珠蛋白基因为研究模型，系统地分析蛋白质赖氨酸甲基转移酶Suv4-20h1/2介导的组蛋白H4K20多甲基化（H4K20me2/3）表观遗传修饰与epsilon-珠蛋白基因表达的关系，探明组蛋白H4K20多甲基化与DNA甲基化以及组蛋白其它标记修饰的可能关联模式。在此基础上，进一步解析组蛋白H4K20多甲基化的识别新特征，破译Suv4-20h1/2介导的表观遗传学密码，阐明人epsilon-珠蛋白基因发育沉默表达的调控新机制并进行体内、体外实验验证。这些研究为重新激活成人细胞中沉默表达的早期珠蛋白基因从而靶向治疗镰刀型细胞贫血和beta-地中海贫血病打下良好的理论基础。

真核基因的转录广泛受到组蛋白修饰和DNA甲基化的调节。然而，多年来关于组蛋白H4K20甲基化与基因表达调控关系的机制研究并不够深入。本项目应用人珠蛋白基因为研究模型，系统地分析了蛋白质赖氨酸甲基转移酶Suv4-20h1/2介导的组蛋白H4K20多甲基化（H4K20me2/3）表观遗传修饰与epsilon-珠蛋白基因表达的关系，探明组蛋白H4K20多甲基化与DNA甲基化以及组蛋白其它标记修饰的关联模式。在此基础上，体内、体外实验验证人epsilon-珠蛋白基因发育沉默表达受组蛋白H4K20多甲基化的调控新机制。这些研究为重新激活成人细胞中沉默表达的早期珠蛋白基因从而靶向治疗镰刀型细胞贫血和beta-地中海贫血病打下良好的理论基础。

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