IMPACT AND DYNAMICS OF DNA METHYLATION IN HUMAN CELLS

描述(改编自研究人员摘要)：CPG甲基化已被 与转录调控、基因组印记和发育有关。CPG 甲基化在复制和分化过程中受到严格调控 体细胞。甲基化模式的改变也经常发生 在癌症中观察到的。虽然甲基化模式的变化在 发育和致癌已被广泛研究，其机制 甲基化的变化还没有被研究过。了解影响和 DNA甲基化的机制可以为人类疾病提供洞察 最近发现是由甲基化相关基因突变引起的。它有 一直是研究人员的目标，以剖析DNA甲基化对 利用异构体系统转录和去甲基化的机制 它们是在过去三年的资助期内发展起来的。他们 在了解这些事件方面取得了重要进展。在下一个 几年后，他们想继续利用这一简化 系统测试以下假设：(1)蛋白质结合可以保护位点 从从头开始的甲基化。(2)甲基化介导组蛋白去乙酰化是一种 局部效应只影响最直接的核小体。(3)MeCP2 对CpG贫乏和CpG丰富的DNA的影响不同。他们还希望进一步 研究染色体中的一些相同的事件和过程 染色体整合系统。这将允许直接比较 上体和集成系统。如果这些事件和过程是相同的 在雌雄异体和染色体上，可以更多地使用异体系统 积极研究内源基因的甲基化过程。如果不同 在这两个制度中都找到了理解这些的基础 不同之处还将提供有关DNA动态的见解 甲基化。

DESCRIPTION (Adapted from investigator's abstract): CpG methylation has been linked to transcriptional regulation, genomic imprinting, and development. CpG methylation is tightly regulated during replication and differentiation of somatic cells. Alteration of methylation patterns has also been frequently observed in cancers. Although changes of methylation patterns during development and carcinogenis have been studied extensively, the mechanisms of the methylation changes have not been explored. Understanding of the impact and mechanism of DNA methylation could provide insights into human diseases recently found to be caused by mutations in methylation-related genes. It has been the goal of the investigators to dissect the impact of DNA methylation on transcription and the mechanism of demethylation utilizing the episomal system that they have developed in the past three years of the funding period. They have made important progress in the understanding of these events. In the next few years, they would like to continue to take advantage of this simplified system to test the following hypotheses: (1) Protein binding can protect sites from de novo methylation. (2) Methylation-mediated histone deacetylation is a local effect that only impacts the most immediate nucleosomes. (3) MeCP2 affects CpG poor and CpG rich DNA differently. They would also like to further investigate some of the same events and processes in the chromosomes using chromosomally integrated systems. This will allow direct comparison of the episomal and the integrated systems. If these events and processes are the same on the episome and in the chromosome, the episomal system can be used more aggressively to study methylation processes of endogenous genes. If differences in these two systems are found, the understanding of the basis of these differences will also provide insights regarding the dynamics of DNA methylation.