MECHANISM OF ABERRANT DNA METHYLATION IN MOUSE LYMPHOMAGENESIS

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 染色体DNA的胞嘧啶甲基化代表了一种可遗传的表观遗传机制来控制基因转录。这一机制在几乎所有人类肿瘤中都被解除了调控，经常导致肿瘤抑制基因的启动子高甲基化及其转录沉默。因此，抑制DNA甲基化机制导致这些基因在肿瘤细胞中重新表达是抗癌治疗的一个有吸引力的可能性。然而，控制肿瘤中异常DNA甲基化模式产生的信号的性质尚不清楚，因此阻碍了我们设计更有效的治疗策略的努力。 三种DNA甲基转移酶DNMT1、DNMT3a和Dnmt3b被认为在正常发育和癌症中产生和维持DNA甲基化模式。到目前为止，单个酶对肿瘤整体甲基化模式的相对贡献还没有得到解决。为了了解DNA甲基转移酶在肿瘤发生过程中产生异常甲基化格局中的作用，本研究计划将重点放在对DNA甲基转移酶缺乏的小鼠淋巴瘤DNA甲基化的全基因组分析上：该建议的具体目的是：1)利用小鼠转基因和基因敲除模型和全基因组方法分析DNA甲基转移酶在正常和恶性造血中的功能。2.)目的：探讨以DNMT1、DNMT3a、DNMT3b及其靶标为靶点进行抗癌治疗的可行性。3.)从机制上了解正常和肿瘤环境中DNA甲基化与组蛋白修饰在转录调控中的协同作用。 总之，这些研究将阐明Dnmt1、DNMT3a和Dnmt3b在小鼠造血和淋巴癌发生中的作用，并将极大地增强我们对调控转录调控的表观遗传事件的理解。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Cytosine methylation of chromosomal DNA represents a heritable epigenetic mechanism to control gene transcription. This mechanism is deregulated in virtually all human tumors frequently leading to promoter hypermethylation of tumor suppressor genes and their transcriptional silencing. Inhibition of DNA methylation machinery resulting in re-expression of these genes in tumor cells therefore represents an attractive possibility for anticancer therapies. However, nature of signals governing the generation of aberrant DNA methylation patterns in tumors is poorly understood, thus hampering our effort to design more efficient therapeutic strategies. Three DNA methyltransferases  DNMT1, DNMT3A and DNMT3B  are thought to generate and maintain DNA methylation patterns during normal development and in cancer. A relative contribution of individual enzymes to global methylation patterns in tumors has not been addressed to date. To understand the role of DNA methyltransferases in generating aberrant methylation landscape during tumorigenesis, this research proposal will focus on genome-wide analysis of DNA methylation in mouse lymphomas deficient for DNA methyltransferases: Specific Aims of this proposal are: 1.) To dissect functions of DNA methyltransferases in normal and malignant hematopoiesis utilizing mouse transgenic and knockout models and global genome-wide approaches. 2.) To test the feasibility of targeting individual enzymatic activities of Dnmts (Dnmt1, Dnmt3a, Dnmt3b and their targets) for anti-cancer therapies. 3.) To understand mechanistically the cooperation of DNA methylation with histone modifications in regulation of transcription in normal and tumor setting. Altogether, these studies will elucidate the role of Dnmt1, Dnmt3a and Dnmt3b in mouse hematopoiesis and lymphomagenesis and will substantially enhance our understanding of epigenetic events governing transcriptional regulation.