Nucleome Therapeutics and Oxford University scientists have mapped the 3D structure of DNA inside living cells at base pair resolution for the first time, revealing new insights into how genes are controlled and offering a framework for discovering novel drug targets.

The study, published in Cell, describes how researchers at the MRC Weatherall Institute of Molecular Medicine used Micro Capture-C (MCC) technology to visualise chromatin structure in unprecedented detail. The approach shows how regulatory elements in the non-coding genome interact with the genes they control, providing a clearer understanding of how genetic variation contributes to disease.

Nucleome Therapeutics holds an exclusive licence from Oxford University for MCC and has applied the technology to uncover the molecular basis of inflammatory diseases by analysing thousands of non-coding disease-associated variants in patient samples.

Mark Bodmer, chief executive officer of Nucleome, said: “Congratulations to James and his team at Oxford on this groundbreaking work. Using MCC technology, for the first time it has been possible to see 3D interactions in the nucleus inside the cell at base pair resolution. This gives us a new way of looking at how genetic variation in the human genome causes disease. At Nucleome, we are applying this transformative technology to solve the molecular basis of inflammatory diseases.”

He added that the company has already identified hundreds of novel drug targets and molecular endotypes, enabling it to build a therapeutic pipeline designed to restore health in inflammatory disorders.

Lead author James Davies, professor at Oxford University and founder of Nucleome Therapeutics, said: “For the first time, we can see how the genome’s control switches are physically arranged inside cells. This changes our understanding of how genes work and how things go wrong in disease.”

The Oxford team developed a new variant of MCC, known as MCC ultra, which captures the physical interactions between DNA segments at single-base resolution. This level of precision allows scientists to see how chromatin folds to bring regulatory regions and genes together — interactions that determine when and where genes are switched on or off.

Over 90% of genetic changes linked to common diseases lie outside genes, in regulatory “switch” regions. Understanding how these switches are organised could accelerate the identification of targets for new medicines.

The work also involved collaboration with Rosana Collepardo-Guevara at the University of Cambridge, whose computational models confirmed that the observed DNA folding patterns arise naturally from the physical properties of DNA and its associated proteins.

Funded by the Medical Research Council and the Lister Institute, with support from the Wellcome Trust and the NIHR Oxford Biomedical Research Centre, the research marks a major step forward in decoding how genome structure governs gene function.