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

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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.