Biophysical models of cohesin-mediated 3D genome folding and its role in DNA-based processes

有人提出，DNA折叠的过程称为'环挤压'的凝聚是一个核心的组织原则的基因组构象。该假说认为，环挤压将基因组DNA卷成环，这是一个使染色质纤维“个性化”并使远距离基因座接近的过程。由此产生的染色体DNA的高阶包装被认为对染色体分离和其他基于DNA的processes.In这个项目中，我们将解决一个关键的控制因素是如何控制的'环挤压'过程中的cohesin的重要结构和监管后果。您将使用结构生物学（cryoEM/X射线）和生物化学方法确定潜在的分子机制。为了可视化细胞中的环挤出，我们将使用我们建立的cryoFIB-SEM管道在天然条件下以高分辨率对染色体的构象进行成像。这些方法将允许您在超分子细节上研究对大规模染色体特征的影响。该项目将为控制细胞中染色体结构的机制提供基本见解。我们预计，我们的工作也可能提供洞察人类疾病的病因引起的失调cohesin包括先天性疾病称为“cohesinopathies”和遗传性疾病，如非整倍体和自然流产。

It has been proposed that DNA folding by a process called 'loop extrusion' by cohesin is a central organising principle of genome conformation. The hypothesis is that loop extrusion reels in genomic DNA into loops, a process which 'individualises' chromatin fibres and brings distant loci into proximity. The resulting higher-order packing of chromosomal DNA is thought to have important structural and regulatory consequences for chromosome segregation and other DNA-based processes.In this project we will address how a key control factor controls the 'loop extrusion' process by cohesin. You will determine the underlying molecular mechanism using structural biology (cryoEM/Xray) and biochemical methods. To visualise loop extrusion in cells we will use our established cryoFIB-SEM pipeline to image the conformation of chromosomes under native conditions and at high resolution. These methods will allow you to study the impact on large-scale chromosomal features at supra-molecular detail. The project will provide fundamental insights into the mechanisms that control chromosome structure in cells. We anticipate that our work may also provide insights into the aetiology of human disorders caused by dysregulation of cohesin including congenital diseases called 'cohesinopathies' and genetic disorders such as aneuploidies and spontaneous human abortions.