Gene Silencing in Cancer--A Model System

癌症中的基因沉默——模型系统

• 批准号: 6634080
• 负责人: MITCHELL S TURKER
• 金额: $ 23.78万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-07-01 至 2005-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6634080
• 关键词: DNA footprinting; DNA methylation; adenine phosphoribosyltransferase; binding proteins; binding sites; chimeric proteins; chromatin; complementary DNA; enzyme induction /repression; gene mutation; genetic promoter element; histones; neoplasm /cancer genetics; neoplastic cell; nucleosomes; polymerase chain reaction; tissue /cell culture

DESCRIPTION: (Adapted from the investigator's abstract) Gene silencing events associated with promoter region methylation are common in malignant cells. An unresolved issue for these silencing events is whether promoter region methylation represents the beginning or end of the process. The major goal of this application is to use mouse Aprt to demonstrate that promoter region methylation is the endpoint of a multistep silencing process. Specifically, methyl binding proteins (MBPs), which are known to bind to methylated regions within the genome and to attract repressive complexes, will be used to trigger silencing at a distance from the promoter. Additional experiments will demonstrate that the promoter has a significant, yet imperfect, mechanism to block MBP-induced silencing and that selective processes are sufficient to maintain silencing. Finally, it will be shown that promoter region methylation is the inevitable endpoint of the silencing process, and that this late event serves to stabilize chromatin changes that accompany MBP-mediated silencing at distance. The demonstration of each step of a multistep silencing pathway, which is currently undefined, will provide novel insight into this aberrant process in malignant cells.

描述：（改编自调查员的摘要）基因沉默事件 与启动子区域甲基化相关的甲基化在恶性细胞中很常见。一个 这些沉默事件未解决的问题是发起人区域是否存在 甲基化代表过程的开始或结束。主要目标 该应用是使用鼠标APRT来证明启动子区域 甲基化是多步兵沉默过程的终点。具体来说， 甲基结合蛋白（MBP），已知与甲基化区域结合 在基因组中并吸引抑制性复合物，将用于触发 距离发起人的距离保持沉默。其他实验将 证明启动子具有重要但不完美的机制 阻止MBP引起的沉默，并且选择性过程足以 保持沉默。最后，将显示启动子区域甲基化 是沉默过程的必然终点，而这是迟到的事件 用于稳定伴随MBP介导的沉默的染色质变化 距离。多步静音途径的每个步骤的演示， 目前不确定的，将为这种异常提供新颖的见解 恶性细胞中的过程。

项目成果

Aberrantly silenced promoters retain a persistent memory of the silenced state after long-term reactivation.

异常沉默的启动子在长期重新激活后保留了沉默状态的持久记忆。

• DOI: 10.1016/j.mrfmmm.2010.10.006
• 发表时间: 2011
• 期刊: Mutation research
• 作者: Oyer,JonA;Yates,PhillipA;Godsey,Sarah;Turker,MitchellS
• 通讯作者: Turker,MitchellS