Our DNA is often pictured as a simple spiral, like a piece of rope held taut. But inside cells, it folds into a complex three-dimensional structure, with two meters of DNA scrunched like a headphone wire in a pocket. This bundled architecture plays a crucial role in how genes are switched on and off. Understanding these interactions is key to interpreting genetic studies of disease, and can help develop targeted treatments. 

Genes – the instructions for making proteins – are regulated by two types of DNA regions, called promoters and enhancers. Promoters are located at the start of each gene and directly load the machinery that reads it to produce RNA, a template for making proteins. In contrast, enhancers, which act like ‘molecular switches’ boosting gene activity in the right cell and condition, may be found much further from the genes they control: sometimes many thousands or even millions of DNA letters away. When DNA folds in the 3D space of the cell’s nucleus, these enhancers loop around to physically contact the genes they regulate.  

Understanding how enhancers work and which genes they control is particularly important because genome-wide association studies – large-scale efforts comparing the DNA of thousands of people to identify small genetic differences linked to disease – have revealed many genetic variants associated with complex conditions such as Crohn’s disease that sit within these regions. Crohn’s Disease is a common form of Inflammatory Bowel Disease, which affects around one in a hundred people globally and currently has no known cure.  

Mapping the 3D genome in rare immune cells connects genes with disease variants  

In a new study published today in Nature Genetics, a team led by Dr Mikhail Spivakov, Head of the Functional Gene Control Group at the LMS, has used a new technology to study the 3D folding of DNA in a rare but important population of immune cells called ILC3s. These cells are known to play a role in inflammation and tissue repair at barrier tissues such as the gut and have been increasingly linked to autoimmune conditions such as Crohn’s disease.  

In their earlier work, Mikhail’s team and collaborators revealed the power of mapping 3D DNA folding for pinpointing the genes affected by disease-causing genetic variants. They used a high-resolution technique called Capture Hi-C for this analysis. At the time, this technique required many millions of cells as input material, making it impossible to apply to rare cell types such as ILC3s. 

To overcome this roadblock, the study’s joint-first author, Professor Valeriya Malysheva, while a postdoctoral researcher in Spivakov’s lab, developed a technology called mini-Capture Hi-C for profiling 3D DNA folding using dramatically fewer cells. Applied to ILC3s, this approach allowed the team to successfully identify the enhancers that physically interact with each gene in these rare cells and connect disease-linked mutations at enhancers with the genes they are most likely to influence.  

“By mapping the 3D contacts between genes and enhancers, we can unlock the power of genome-wide association studies, implicating new genes and pathways in disease traits”, said Mikhail. 

Using this approach, the researchers detected over 100 genes in ILC3s that are likely affected by enhancer variants that increase the risk of Crohn’s disease. About half of these genes had known roles in this disease, but the rest were not previously linked with this condition. Many of these genes are involved in key immune processes in ILC3s that help the body respond to tissue damage and infection, but can also drive disease when dysregulated. 

By linking distant regulatory elements to their target genes, the study provides a clearer picture of how subtle genetic differences can alter immune cell behaviour – for example, by increasing or dampening the production of inflammatory molecules. 

A new role for a neurological disease gene in the immune system  

Among the genes that the team linked with Crohn’s disease through their contacts with affected enhancers in ILC3s is CLN3, a gene previously associated with the neurodegenerative disorder Batten disease. 

“Finding a neurological gene like CLN3 active in gut immune cells was a fascinating surprise, showing the power of using data-driven genome-wide integrative approaches. Building on mini-PCHi-C and the computational tools previously developed in Mikhail’s lab, we were able to probe the complex 3D genomics of these rare cells and reveal new mechanisms of disease”, said Valeriya, now a Fellow at the University of Cambridge and group leader at the VIB Center for Molecular Neurology in Antwerp. 

To validate this finding, joint-first author Nora Lakes, a PhD student at Cincinnati Children’s Hospital Medical Center, performed extensive validation experiments, confirming that CLN3 directly influences how strongly ILC3s produce inflammatory signals. 

 “Our work reveals a previously unrecognised role for this gene in the immune system, highlighting its multifaceted role and potentially shedding light on connections between the neural system and the gut, which have become clearer in recent years. We’ve shown that this gene regulates the inflammatory function of ILC3s, but it will take more research to establish exactly how this modulates Crohn’s disease risk and whether these pathways can be targeted in future treatments”, said Dr Helen Ray-Jones, joint-first author, based at Erasmus MC University Medical Center, Rotterdam. 

More broadly, the study expands the range of genes that contribute to autoimmune disease risk and highlights the importance of studying the molecular mechanisms of gene regulation to interpret genetic associations.  

 “The more we know about the genes that mediate disease risk and understand disease mechanisms, the more we can design novel targeted treatments”, concludes Mikhail. 

This work was a truly interdisciplinary effort, bringing together researchers in computational and experimental genomics, population genetics and immunology across continents, demonstrating the power of such research partnerships in discovering new fascinating and clinically relevant biology. It was carried out in collaboration with researchers at VIB Center for Molecular Neurology, Belgium, Cincinnati Children’s Hospital Medical Center, USA and multiple other teams in Europe and the United States. 

The study was primarily funded by the Medical Research Council and National Institutes of Health. 

Read the full publication: https://www.nature.com/articles/s41588-026-02681-0