Multi-million pound study aims to unravel key mystery in genome regulation

Academics from the University of Leicester are leading a pioneering study to investigate how three-dimensional organisation of our genomes contributes to the regulation of genome function.

While we understand the linear sequence of DNA, the three-dimensional organisation of the genome within the nucleus remains a mystery. The dynamic spatial arrangement of chromosomes and the functional consequences of specific configurations are important for genome repair, replication, transcription, and recombination, all fundamental aspects of life. 

A protein termed cohesin plays a central role in 3D spatial genome organisation but how it can control such diverse biological processes has been a mystery. 

Professor Daniel Panne from the Leicester Institute for Structural and Chemical Biology will lead the research in collaboration with colleagues from Imperial College London, University of Oxford and the Netherlands Cancer Institute.

He said: “How cohesin controls such diverse biological processes is a major question in genome biology. Addressing this knowledge gap is important because the processes coordinated by cohesin are central to human development, homeostasis and disease.

“We will look at how cohesin controls genomic processes and how cohesin function is regulated by a network of interacting proteins through a collaborative, interdisciplinary approach that combines our expertise in structural biology, biochemistry, cell biology, model organisms and integrative imaging across scales. 

“Our inter-disciplinary team and its combined expertise will allow us to address questions and operate across scales in a manner that breaks technical boundaries that would be impossible to tackle by a single lab.”

The study has been made possible through a prestigious 6-year Wellcome Discovery Award of £2.8m. Work is set to begin next month and will utilise facilities across all four institutes including the University of Leicester’s Cryo-Electron Microscopy Facility which houses one of the most powerful microscopes available to process samples at high resolution. It will also make use of cryo-ET - correlative light and electron microscopy (CLEM) - at the University of Oxford.

Professor Panne’s expertise has already led to other key information into how cohesin is regulated. A study published last year revealed fundamental insights into how the iconic X shape of mitotic chromosomes is formed.

Professor Panne said: “Earlier work has revealed that cohesin interacts with a network of distinct chromosomal regulators to control genome function. We will now identify and characterise key players in this network, uncover the underlying mechanisms and dissect how cohesin affects major biological processes. Our project will use inter-disciplinary and innovative approaches across atomic, cellular and organismal scales and will provide a significant shift in our understanding of how 3D genome organisation is regulated. 

“Understanding cohesin's diverse functions in genome regulation is crucial for unravelling its impact on human health and disease. Disruptions in cohesin or its associated factors can lead to aberrant 3D genome architecture and can affect gene regulation, genomic stability and contribute to the development of diseases. Insights into the molecular mechanisms may lead to the development of targeted therapies for conditions associated with cohesin dysfunction including different cancer types and developmental disorders.”