IMPACT AND DYNAMICS OF DNA METHYLATION IN HUMAN CELLS

DNA 甲基化对人类细胞的影响和动力学

• 批准号: 6197439
• 负责人: Chih-Lin Hsieh
• 金额: $ 26.98万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-09-01 至 2004-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6197439
• 关键词: DNA binding protein; DNA methylation; acetylation; alleles; developmental genetics; early embryonic stage; gene expression; genetic promoter element; genetic recombination; genetic regulation; genetic regulatory element; genomic imprinting; histones; human genetic material tag; laboratory mouse; protein binding; tissue /cell culture; transcription factor; transfection /expression vector

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.

描述（改编自研究者摘要）： 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的调控， 体细胞甲基化模式的改变也经常发生在 在癌症中观察到。虽然甲基化模式的变化， 发展和致癌已被广泛研究， 甲基化的变化还没有被研究。了解影响和 DNA甲基化机制可以为人类疾病提供见解 最近发现是由甲基化相关基因突变引起的。它有 研究人员的目标是剖析DNA甲基化对 利用附加体系统的转录和去甲基化机制 他们在过去三年的资助期内开发的。他们 在理解这些事件方面取得了重要进展。未来 几年后，他们希望继续利用这种简化的 系统来检验以下假设：（1）蛋白结合可以保护位点 从头甲基化。(2)甲基化介导的组蛋白去乙酰化是一种新的机制。 仅影响最直接的核小体的局部效应。(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事件和过程， 染色体整合系统。这将允许直接比较 游离型和整合型系统。如果这些事件和过程是相同的 在附加体和染色体上，附加体系统可以更多地使用 积极研究内源基因的甲基化过程。差异是否 在这两个系统中发现，这些基础的理解 这些差异也将提供有关DNA动力学的见解， 甲基化