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

在哺乳动物中，DNA甲基化是参与重要生物学现象的长期基因沉默的主要参与者之一。在许多情况下，已经发现核小体重塑和组蛋白脱乙酰化（NuRD）复合物介导由甲基化DNA以及由DNA结合的转录阻遏物引起的沉默。基于我们的发现，即（a）存在几种NuRD复合物，（B）NuRD与甲基化DNA的结合是通过与甲基CpG以外的组蛋白尾部结合介导的，以及（c）SUMO化（小泛素样修饰物的共价结合）诱导NuRD组分缔合和转录抑制，我们可以分析特定NuRD变体的特定功能。此外，通过使用生物化学和细胞学工具，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，我们将分析如何抑制标记扩散到活性染色质。SUMO化的作用将通过将NuRD功能分离为组装、顺序修饰和抑制性标记的扩散的单个事件来研究。这可能使我们能够解决SUMO之谜，这是发现几乎所有的SUMO化的蛋白质，并描述了一个事实，即少数SUMO化的蛋白质发挥主要作用。

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.