基因印记和DNA甲基化的维持机理的研究

项目名称： 基因印记和DNA甲基化的维持机理的研究

项目编号： No.31471211

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 生物科学

项目作者： 颉伟

作者单位： 清华大学

项目金额： 100万元

中文摘要： 基因印记是一种基于亲本的单等位基因表达的现象。这种现象在哺乳动物中通常只出现在几百个特殊的基因上，但这些基因包含很多重要的细胞生长因子或者是抑癌基因。它们的正常表达是动物发育所必需的。基因印记由等位基因差异性DNA甲基化所控制。这种差异性DNA甲基化在配子形成的时候建立，并能够在细胞分化和个体发育过程中稳定地遗传下去，甚至不受胚胎发育早期基因组大规模去甲基化重编程的影响。然而基因印记经常在癌症细胞中发生异常，而基因印记的缺失也在小鼠中被证明能够促进癌症的发生。到现在为止，基因印记是如何在发育过程中稳定遗传，并逃脱DNA去甲基化的影响，它们在癌症细胞中又是如何失调的，这些问题仍然是未知的。申请人将重点研究DNA甲基化是如何在基因印记区域和其他一些基因组区域稳定遗传的，这种机制在肿瘤细胞中又是如何紊乱的。这些研究将为阐明动物发育和相关疾病的表观遗传调控提供理论支持。

中文关键词： DNA甲基化；表观遗传学；组蛋白修饰；表观遗传调控；转录调控

英文摘要： Genomic imprinting is defined as parent-of-origin dependent monoallelic expression of a subset of genes, many of which encode critical cell growth regulators and tumor suppressors. Genomic imprinting, which is essential for embryogenesis, is controlled by allele specific DNA methylation known as imprints. Once established during gametogenesis, these genomic imprints are stably maintained throughout development, even surviving a dramatic global demethylation wave during preimplantation embryogenesis. However, genomic imprints are frequently altered in cancer and the loss of imprinting (LOI) has been shown to promote tumorigenesis. Currently, the mechanisms underlying the resistance of genomic imprints to demethylation and their misregulation in cancer are not well understood. Elucidating these molecular principles is essential for both understanding mammalian development and cancer treatment. Recently, we have identified by far the largest number of genomic imprint candidates in mice. In my proposed research, we will examine the mechanism by which DNA methylation is maintained at these imprinted loci and elsewhere during early development, and how misregulation of such mechanism may contribute to the altered epigenetic landscape and gene transcription in cancer. The proposed study will elucidate the fundamental principles of epigenetic regulation of mammalian development, and shed light on the etiology of epigenetics related human diseases including cancer.

英文关键词： DNA methylation;Epigenetics;Histone modification;Epigenetic regulation;Transcription regulation