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

有人提出，DNA折叠是基因组构象的一个中心组织原则，这个过程被称为粘附素‘环挤出’。假设是环状挤压将基因组DNA卷绕成环状，这一过程使染色质纤维“个体化”，并使遥远的基因座接近。由此产生的染色体DNA的高序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控后果。在这个项目中，我们将讨论一个关键控制因素如何通过粘附素控制“环挤出”过程。您将使用结构生物学(低温电子显微镜/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。这些方法将使你能够研究超分子细节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的见解。我们预计，我们的工作还可能为研究凝集素调节失调引起的人类疾病的病因学提供洞察力，包括称为粘附素病的先天性疾病，以及非整倍体和自然流产等遗传疾病。

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.