Understanding how the NuRD complex regulates ES cell differentiation using single molecule fluorescence imaging

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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 cell in the body.The project brings together a unique combination of skill sets, in biochemistry/structural biology, single molecule imaging, and stem cell biology, to develop single molecule approaches for studying nuclear processes in mammalian cells. Up to now most work in this field has focussed on studies of processes occurring on either the cell surface or in bacterial cells. We have carried out a great deal of preliminary work to demonstrate feasibility (and thus reduce the risk), such that we can now envisage a highly inter-disciplinary research program to study the way the NuRD complex interacts with chromatin, and how this controls gene expression during ES cell differentiation. 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. In a related project we are attempting to develop small molecule inhibitors and activators of NuRD complexes to control chromatin structure. Our research may thus in the long-term facilitate our ability to directly influence gene expression profiles, stem cell differentiation and disease.