MECHANISM OF ABERRANT DNA METHYLATION IN MOUSE LYMPHOMAGENESIS

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 染色体DNA的胞嘧啶甲基化代表了控制基因转录的可遗传的表观遗传机制。这一机制在几乎所有人类肿瘤中都是失调的，经常导致肿瘤抑制基因的启动子超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代表了抗癌疗法的有吸引力的可能性。然而，控制肿瘤中异常DNA甲基化模式产生的信号的性质知之甚少，从而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  DNMT 1、DNMT 3A和DNMT 3B  被认为在正常发育和癌症中产生并维持DNA甲基化模式。 迄今为止，尚未解决单个酶对肿瘤中全局甲基化模式的相对贡献。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景观的作用，本研究计划将专注于DNA甲基转移酶缺陷小鼠淋巴瘤中DNA甲基化的全基因组分析：本计划的具体目的是：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.）的情况。测试针对Dnmts（Dnmt 1、Dnmt 3a、Dnmt 3b及其靶标）的单个酶活性用于抗癌疗法的可行性。3.）第三章了解DNA甲基化与组蛋白修饰在正常和肿瘤环境中转录调控的机制。总之，这些研究将阐明Dnmt 1，Dnmt 3a和Dnmt 3b在小鼠造血和淋巴瘤发生中的作用，并将大大提高我们对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. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. 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.