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

有人提出，DNA折叠的过程被称为“环挤压”的粘聚蛋白是基因组构象的中心组织原则。这个假设是，环挤压使基因组DNA绕成环，这一过程使染色质纤维“个性化”，并使遥远的位点靠近。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的过程具有重要的结构和调节后果。在这个项目中，我们将讨论一个关键的控制因素是如何通过粘合来控制“循环挤压”过程的。您将使用结构生物学（cryoEM/ x射线）和生化方法确定潜在的分子机制。为了可视化细胞中的环挤压，我们将使用我们建立的cryoFIB-SEM管道在自然条件下以高分辨率成像染色体的构象。这些方法将使您能够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关于由黏结蛋白失调引起的人类疾病的病因学的见解，包括称为“黏结病”的先天性疾病和遗传疾病，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.