Understanding how the NuRD complex assembles and functions in mouse embryonic stem cells (mESC's)

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The Nucleosome Remodeling and Deacetylation (NuRD) protein complex plays a key role in controlling the way our genomes are packaged inside the cell into a structure called chromatin. This packaging in turn controls whether particular genes (sequences of DNA) are/are not expressed. In particular, the NuRD complex controls gene expression as embryonic stem (ES) cells first start to differentiate into all the different types of specialised cells in the body. Without some of the NuRD complex components, ES cells cannot differentiate at all, clearly demonstrating its importance. So how does the NuRD complex form? And how does it affect gene expression in ES cells? These are the questions we hope to answer.Up until now, we (and the field as a whole) have focussed on trying to understand which components make up the NuRD complex, which regions of the genome it interacts with, and which genes are affected by it. However, we have recently shown that we can make the individual components and assemble the NuRD complex outside of a cell. This will allow us to study its structure and how it interacts with the small regions of the genome to which it binds. We have shown using cutting-edge imaging that we can track single NuRD complex components inside a cell and watch in real-time how they assemble on chromatin. We can also study how the NuRD complex affects the binding of other proteins, and ultimately gene expression. We now envisage a highly inter-disciplinary research program that combines these approaches to determine the structure of the NuRD complex, understand how NuRD complexes assemble and interact with different parts of the genome, and how they control gene expression. Our long-term goal is to use this understanding to control the differentiation of stem cells. This understanding when applied to either ES cells, or adult cells that have been induced to become stem cells (iPS cells), could have enormous potential - e.g. for providing a source of human tissue to study disease progression, or to develop drugs for personalised molecular therapies. We will also attempt to develop small molecule inhibitors and activators of NuRD complexes to control chromatin structure. Our research may in the long-term facilitate our ability to directly influence gene expression profiles, stem cell differentiation and disease.