A new study published in Nature Genetics reveals how the three-dimensional organization of DNA in rare immune cells helps explain the genetic risk for Crohn’s disease and other autoimmune conditions, according to research co-led by Prof. Valeriya Malysheva, group leader at the VIB-UAntwerp Center for Molecular Neurology. Rather than viewing the genome as a simple linear sequence, the international research team focused on how DNA folds in physical space, bringing distant regulatory regions into contact with the genes they control.
Mapping 3D Genome Architecture in Rare Immune Cells
Understanding three-dimensional architecture is crucial for gene regulation and mapping how disease-associated genetic variants exert their effects, according to the published study. Researchers focused on innate lymphoid cells (ILC3s), a rare population of immune cells involved in inflammation and tissue repair at barrier surfaces like the gut. Although these cells are increasingly implicated in autoimmune disease, they have remained difficult to study at the genome regulation level due to their extreme scarcity.
Did you know? Traditional genome mapping methods require millions of cells, making it nearly impossible to study rare immune populations without pooling samples and losing critical regulatory detail.
Miniaturized Capture Hi-C Solves Cell Scarcity
That technical barrier was addressed using miniaturized Capture Hi-C, a method developed by Prof. Valeriya Malysheva during her postdoctoral work at the MRC Laboratory of Medical Sciences in the UK. This approach makes it possible to map long-range DNA interactions in rare cell populations using far fewer cells than conventional techniques require. When applied to ILC3s, the method allowed the global research team to directly connect disease-associated genetic variants in regulatory DNA regions to the specific genes they regulate.
Uncovering Over 100 Genes Linked to Crohn’s Disease Risk
Using this strategy, researchers identified more than 100 genes in ILC3s that may be influenced by regulatory variants associated with Crohn’s disease risk. According to the findings, about half of these genes were already known players in the condition, while the remaining targets had not previously been linked to the disease. This spatial map provides a clearer blueprint of the cellular mechanisms driving chronic gut inflammation.
Frequently Asked Questions
What are innate lymphoid cells (ILC3s)?
ILC3s are a rare population of immune cells that play a central role in driving inflammation and tissue repair, particularly at barrier tissues like the human gut.
How does 3D DNA folding affect autoimmune disease risk?
DNA folding brings distant regulatory regions of the genome into physical contact with target genes, meaning genetic variants located far from a gene can still control its activity and influence disease susceptibility.
What is miniaturized Capture Hi-C?
Developed by Prof. Valeriya Malysheva, it is an innovative laboratory method that maps long-range DNA interactions in rare cell populations using significantly fewer cells than standard mapping protocols.
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