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

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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.