Differential functions of the Nucleosome Remodelling and Histone-Deacetylase (NuRD) complex components

核小体重塑和组蛋白脱乙酰酶 (NuRD) 复合物成分的差异功能

• 批准号: 44028142
• 负责人: Professor Dr. Rainer Renkawitz
• 金额: --
• 依托单位: Institut für Genetik
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2007
• 资助国家: 德国
• 起止时间: 2006-12-31 至 2011-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/44028142?language=en
• 关键词: Differential; functions; Nucleosome; Remodelling; Histone

In mammals, DNA methylation is one of the main players of long-term gene silencing involved in important biological phenomena. In many cases, the Nucleosome Remodelling and Histone Deacetylation (NuRD) complex has been found to mediate silencing caused by methylated DNA as well as by DNA bound transcriptional repressors. Based on our findings that (a) several NuRD complexes exist, (b) that NuRD binding to methylated DNA is mediated by binding to histone tails in addition to methyl CpG and (c) that SUMOylation (covalent binding of the small ubiquitin-like modifier) induces NuRD component association and transcriptional repression, we can analyze specific functions of specific NuRD variants. Furthermore, by using biochemical as well as cytological tools, we will address the causal relationship between DNA methylation, histone deacetylation and histone methylation and we will analyze how a repressive mark spreads into active chromatin. The role of SUMOylation will be studied by separating NuRD functions into the individual events of assembly, sequential modifications and spreading of the repressive mark. This may allow us to solve the SUMO enigma , which is found for almost all SUMOylated proteins, and is described by the fact that a minority of a SUMOylated protein exerts a major effect.

在哺乳动物中，DNA甲基化是长期基因沉默的主要参与者之一，涉及重要的生物现象。在许多情况下，已经发现核小体重塑和组蛋白去乙酰化（NuRD）复合物介导由甲基化DNA和DNA结合的转录抑制因子引起的沉默。基于我们的发现(a)存在几种NuRD复合物，(b)除了甲基CpG外，NuRD与甲基化DNA的结合是通过与组蛋白尾巴的结合介导的，以及(c) SUMOylation（小泛素样修饰子的共价结合）诱导NuRD组分关联和转录抑制，我们可以分析特定NuRD变体的特定功能。此外，通过使用生化和细胞学工具，我们将解决DNA甲基化，组蛋白去乙酰化和组蛋白甲基化之间的因果关系，我们将分析抑制标记如何扩散到活性染色质。SUMOylation的作用将通过将NuRD功能分离为组装、序列修饰和抑制标记扩散的单个事件来研究。这可能使我们能够解决几乎所有SUMO化蛋白都存在的SUMO之谜，它是由一个事实描述的，即一个SUMO化蛋白的少数发挥主要作用。