MECHANISM OF ABERRANT DNA METHYLATION IN MOUSE LYMPHOMAGENESIS

小鼠淋巴细胞发生中异常 DNA 甲基化的机制

• 批准号: 8168389
• 负责人: Rene Opavsky
• 金额: $ 11.74万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8168389
• 关键词: Aberrant DNA Methylation; Address; Computer Retrieval of Information on Scientific Projects Database; Cytosine; DNA; DNA Methylation; DNA Methylation Inhibition; DNA Methyltransferase; DNA Modification Methylases; Development; Enzymes; Epigenetic Process; Event; Funding; Gene Expression; Generations; Genetic Transcription; Grant; Hematopoiesis; Human; Hypermethylation; Individual; Institution; Knock-out; Lymphoma; Lymphomagenesis; Malignant - descriptor; Malignant Neoplasms; Methylation; Modeling; Mus; Nature; Pattern; Relative (related person); Research; Research Personnel; Research Proposals; Resources; Role; Signal Transduction; Source; Testing; Therapeutic; Transcriptional Regulation; Transgenic Mice; Tumor Suppressor Genes; United States National Institutes of Health; cancer therapy; design; genome wide association study; genome-wide; genome-wide analysis; histone modification; neoplastic cell; promoter; tumor; tumorigenesis

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.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 染色体DNA的胞嘧啶甲基化代表了控制基因转录的一种可遗传的表观遗传机制。在几乎所有人类肿瘤中，这种机制经常导致肿瘤抑制基因及其转录沉默的启动子过度甲基化。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，这代表了抗癌疗法的有吸引力的可能性。然而，对肿瘤中异常DNA甲基化模式产生的信号的性质知之甚少，从而阻碍了我们为设计更有效的治疗策略而努力。 三种DNA甲基转移酶DNMT1，DNMT3A和DNMT3B被认为在正常发育和癌症过程中产生和维持DNA甲基化模式。 迄今为止尚未解决各个酶对肿瘤中全球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在产生异常的甲基化景观中的作用，该研究建议将重点介绍小鼠淋巴瘤中DN​​A甲基化对DNA甲基转移酶缺乏的DNA甲基化的分析：该建议的特定目的是该建议的特定目的全球全基因组方法。 2.）测试DNMT（DNMT1，DNMT3A，DNMT3B及其靶标）靶向单个酶活性的可行性。 3.）在正常和肿瘤环境下的转录调节中，在机械上理解了DNA甲基化与组蛋白修饰的合作。 总而言之，这些研究将阐明DNMT1，DNMT3A和DNMT3B在小鼠造血和淋巴作用中的作用，并大大增强我们对控制转录调节的表观遗传事件的理解。