Genome control by cohesin ligands

About the Project

Second Supervisor: Professor Peijun Zhang, Nuffield Department of Medicine University of Oxford

The human genome is metres long but packed into cells only a few micrometres in diameter. To function correctly, DNA must be carefully organised so that essential processes such as gene expression, repair, replication, and cell division can occur. A key organiser is the cohesin complex, a ring-shaped protein machine that controls the structure of the genome. Cohesin can connect DNA regions within the same chromosome (“in cis”) by reeling the DNA into loops, or hold sister chromatids together after DNA replication (“in trans”) until they are separated during cell division. Both functions are vital for accurate gene regulation and genome stability.

Cohesin is regulated by partner proteins that determine where it binds, stabilises, or releases DNA. We have shown that several cohesin regulators use a common molecular motif to control cohesin, influencing whether it forms loops or maintains chromosome cohesion. This suggests that many such “ligands” form a broader system that directs cohesin activity at different stages of the cell cycle and across the genome.

This project will investigate how these ligands regulate cohesin’s diverse roles. We will use cutting-edge methods, including single-particle cryo-EM and in cell cryo-ET to visualise protein structures and use biochemical assays and cell-based approaches to test biological outcomes. Together, these studies will reveal how cohesin control links three-dimensional genome organisation to key processes such as gene expression, DNA repair, and chromosome segregation.

Understanding these mechanisms will provide fundamental insights into genome biology and how defects in cohesin regulation contribute to human disease.

Techniques that will be undertaken during the project

1. Recombinant protein complex engineering, expression and purification. In vitro reconstitution.
2. Chromatographic methods for protein purification
3. Single-particle cryoEM workflow (grid preparation and data collection)
4. cryoET workflow including lamella preparation and targeting in situ
5. Computational & quantitative analyses
6. Biochemical analyses

Enquiries

Project Enquiries to daniel.panne@le.ac.uk

To apply please use the application link at the bottom of this web page Molecular and Cell Biology | Postgraduate research | University of Leicester