Researchers have achieved the most detailed view yet of how DNA folds and functions inside living cells, revealing the physical structures that control when and how genes are switched on.
Using a new technique called MCC ultra, the team, including researchers from the University of Cambridge, mapped the human genome down to a single base pair, unlocking how genes are controlled, or, how the body decides which genes to turn on or off at the right time, in the right cells.
This gives scientists a new way to understand how genetic differences lead to disease and opens up fresh routes for drug discovery. The results are reported in the journal Cell.
"For the first time, we can see how the genome's control switches are physically arranged inside cells," said lead author Professor James Davies from the University of Oxford. "This changes our understanding of how genes work and how things go wrong in disease. We can now see how changes in the intricate structure of DNA leads to conditions like heart disease, autoimmune disorders and cancer."
For more than two decades, scientists have known the full sequence of the human genome - the three billion 'letters' of DNA that make up our genetic code. But exactly how that code folds and functions inside the cell has remained largely hidden.
Each cell's DNA, about two metres long, is tightly packed into a microscopic space one-hundredth of a millimetre across. Within this space, the DNA constantly bends and loops, bringing distant sections into contact. These 3D structures are crucial because they determine which genes are active or silent, much like how a circuit board determines which switches are connected and which are not.
Until now, researchers could only view these interactions at relatively low resolution. The new method captures them down to a single base pair - the smallest unit of DNA - offering a truly molecular view of gene control.
This level of detail matters because over 90% of genetic changes linked to common diseases lie not within genes themselves, but in the 'switch' regions that regulate them. The ability to see how these switches are organised gives scientists a new framework for identifying where gene regulation goes wrong and how it might be corrected.
The Oxford researchers worked with Professor Rosana Collepardo-Guevara, from Cambridge's Department of Genetics and Yusuf Hamied Department of Chemistry, whose computer simulations confirmed that the folding patterns observed arise naturally from the physical properties of DNA and its packaging proteins.
"The MCC ultra technique gives us the most detailed view yet of DNA organisation inside living cells - an order of magnitude higher than the current state of the art," said Collepardo-Guevara. "Our simulation work also showed that it's possible to predict the complex 3D structure of the genome in a computer model, which could help us understand in fine detail what goes wrong in disease, and how to fix it."
Together, the scientists propose a new model of gene regulation in which cells use electromagnetic forces to bring DNA control sequences to the surface, where they cluster into "islands" of gene activity. These structures, which were previously invisible, appear to be a fundamental mechanism for how cells read their genetic instructions.
The research represents a major advance in molecular genetics, providing a foundation for future studies into how changes in genome structure cause disease.
The work was funded by the Medical Research Council and the Lister Institute, with support for translation into new therapies from Wellcome and the NIHR Oxford Biomedical Research Centre. Rosana Collepardo-Guevara is a Fellow of Clare College, Cambridge.
Reference:
Hangpeng Li et al. 'Mapping chromatin structure at base-pair resolution unveils a unified model of cis-regulatory element interactions.' Cell (2025). DOI: 10.1016/j.cell.2025.10.013
Adapted from a University of Oxford media release.
