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

核小体重塑和脱乙酰化（NuRD）蛋白复合物在控制我们的基因组在细胞内包装成称为染色质的结构的方式中起着关键作用。这种包装反过来控制特定基因（DNA序列）是否表达。特别是，NuRD复合物控制基因表达，因为胚胎干细胞（ES）首先开始分化为体内所有不同类型的特化细胞。该项目汇集了生物化学/结构生物学，单分子成像和干细胞生物学的独特技能组合，以开发研究哺乳动物细胞核过程的单分子方法。到目前为止，这一领域的大多数工作都集中在细胞表面或细菌细胞中发生的过程的研究上。我们已经进行了大量的初步工作来证明可行性（从而降低风险），因此我们现在可以设想一个高度跨学科的研究计划来研究NuRD复合物与染色质相互作用的方式，以及这如何控制ES细胞分化过程中的基因表达。我们的长期目标是利用这种理解来控制干细胞的分化。当这种理解应用于ES细胞或已被诱导成为干细胞（iPS细胞）的成体细胞时，可能具有巨大的潜力-例如，为研究疾病进展提供人体组织来源，或开发用于个性化分子疗法的药物。在一个相关的项目中，我们正试图开发NuRD复合物的小分子抑制剂和激活剂来控制染色质结构。因此，我们的研究可能会在长期内促进我们直接影响基因表达谱，干细胞分化和疾病的能力。

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.