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Biology-Physics collaboration wins Wellcome Trust funding

University of Edinburgh Professors Nick Gilbert (MRC Human Genetics Unit) and Davide Marenduzzo (School of Physics and Astronomy) will investigate how chromatin structure affects transcription: September 2021

DNA forms the blueprint for all higher organisms, but is itself a complex molecule. Within the nucleus of human cells, DNA is packaged with proteins to form chromatin and organised in dynamic, three dimensional structures. We do not understand well how the structure of DNA and chromatin affects how genes are translated into the messenger molecule, RNA, in a process called transcription.

Two scientists at the University of Edinburgh, Nick Gilbert (MRC Human Genetics Unit) and Davide Marenduzzo (School of Physics and Astronomy) have been collaborating to shed light on this problem and have just been awarded a £2.1M Wellcome Investigator grant to drive their research forward.

Davide Marenduzzo, Professor of Computational Biophysics, explains, “In this project, we wish to find a quantitative relationship between gene structure and transcription in human cells. A direct link between structure and transcription has been postulated to exist on the basis of long-standing experiments, but it has never been demonstrated in practice, as laboratory experiments on their own lack the sufficient resolution.

The key novelty in our approach is the synergistic combination of our experimental and modelling techniques, which allows us to answer questions which it was previously impossible to address. For instance, we are now using simulations to predict the 3D structure and transcriptional activity of all human genes in a given cell type, validating the results experimentally as we go.

This genome-wide approach has already allowed us to find new 3D gene structures which are functionally relevant, and we hope to make new discoveries as our project progresses”.

Nick Gilbert, a Professor of Molecular Biology, says, “For many years lab researchers have been dissecting the fundamental workings of cells and making great strides in their discoveries. However, the questions we are now wanting to ask are often about the dynamics of cellular processes which our lab techniques struggle to answer.

Gilbert/ Marenduzzo
Nick Gilbert (MRC Human Genetics Unit) and Davide Marenduzzo (School of Physics and Astronomy)

To overcome these challenges we started a collaboration (nearly ten years ago) between molecular biology and physics. Although we had to learn to communicate with each other, we had an underlying drive to explore 3D gene folding and the underlying mechanism important for transcriptional regulation. Since then, we have worked closely to build new models to predict how cells work; many of these methods are validated by experiments, so using these fundamental principles we can now predict underlying mechanisms purely from simulations. This is crucial as lab experiments alone are not providing the answers but working together we can explore the ways in which cells work, but also understand what happens when they go wrong, for example in disease.”

The scientists hope their results could be used in the not-distant future to develop a new understanding of how mutations in chromatin-associated proteins, regulatory factors or DNA elements could lead to genetic diseases and cancer.

Links

Nick Gilbert Research Group

Davide Marenduzzo (https://www.ph.ed.ac.uk/people/davide-marenduzzo)