3D DNA organization in rare immune cells can explain Crohn's disease risk

A new study co-led by Prof. Valeriya Malysheva, group leader at the VIB-UAntwerp Center for Molecular Neurology, has been published in Nature Genetics. The work uncovers how the three-dimensional organization of DNA in rare immune cells can help explain genetic risk for Crohn's disease and other autoimmune conditions.

Rather than viewing the genome as a simple linear sequence, the study focuses on how DNA folds in space inside our cells, bringing distant regulatory regions into physical contact with the genes they control. This 3D architecture is crucial for gene regulation, and understanding it can help explain how disease-associated genetic variants exert their effects.

In the new study, a global research team focuses on a specific type of innate lymphoid cells (ILC3s), a rare population of immune cells involved in inflammation and tissue repair at barrier tissues such as the gut. Although these cells have increasingly been implicated in autoimmune disease, they have remained difficult to study at the level of genome regulation because of their scarcity.

That issue is now addressed through the use of miniaturized Capture Hi-C, a method developed by Prof. Valeriya Malysheva (VIB-UAntwerp), during her postdoctoral work at the MRC Laboratory of Medical Sciences in the UK. The approach makes it possible to map long-range DNA interactions in rare cell populations using far fewer cells than conventional methods require. Applied to ILC3s, it allowed the team to connect disease-associated genetic variants in regulatory DNA regions to the genes they are most likely to affect.

Using this strategy, the researchers identified more than 100 genes in ILC3s that may be influenced by regulatory variants associated with Crohn's disease risk. About half were already known players in the disease, while the others had not previously been linked to it.

One particularly striking finding was the implication of CLN3, a gene best known for its role in the neurodegenerative disorder Batten disease. In follow-up experiments, we showed that this gene directly influences how strongly the cells produce inflammatory signals, revealing its unexpected role in the immune system. This result demonstrates the power of genome-wide integrative approaches to uncover unexpected connections, including those between the nervous and immune systems."

Prof. Valeriya Malysheva, group leader, VIB-UAntwerp Center for Molecular Neurology