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

粘连蛋白介导的 3D 基因组折叠的生物物理模型及其在基于 DNA 的过程中的作用

• 批准号: 2738561
• 金额: --
• 依托单位: University of Leicester
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2738561
• 关键词: Biophysical; models; cohesin; mediated; 3D

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.

有人提出，通过粘连蛋白“环挤压”的过程进行的 DNA 折叠是基因组构象的核心组织原理。假设是环挤压将基因组 DNA 卷入环中，这一过程使染色质纤维“个体化”并使遥远的基因座变得接近。由此产生的染色体 DNA 的高阶堆积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，我们将解决关键控制因素如何通过粘连蛋白控制“环挤出”过程。您将使用结构生物学（冷冻电镜/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管道在天然条件下以高分辨率对染色体构象进行成像。这些方法将使您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染色体结构的机制提供基本见解。我们预计我们的工作还可以深入了解由粘连蛋白失调引起的人类疾病的病因学，包括称为“粘连蛋白病”的先天性疾病和遗传性疾病，例如非整倍体和人类自发流产。