Genetic risk for autoimmune disease may be hiding in the spaces between genes. A study published in Nature Genetics has revealed how disease-associated DNA variants can regulate genes located far away along the chromosome by mapping the three-dimensional structure of the genome in rare human immune cells. The work focuses on type 3 innate lymphoid cells, or ILC3s, which help protect tissue barriers and regulate inflammation but have been difficult to study because they are scarce and do not readily multiply outside the body.
The findings offer a more precise view of how inherited risk may contribute to diseases such as Crohn’s disease. Rather than assuming that a disease-linked variant affects the nearest gene, the researchers traced physical contacts between regulatory DNA regions and gene promoters—the DNA sequences that control gene activation. Their results show that the genome behaves less like a straight line and more like a densely folded molecular network, allowing regulatory elements to influence genes located thousands or even millions of DNA bases away.
ILC3s are found primarily in tissues, including the intestine, where they support barrier integrity and coordinate immune responses. They can produce inflammatory signaling molecules, or cytokines, that help defend the body but may also contribute to chronic inflammation when improperly regulated. Because ILC3s are rare in human tissue, conventional techniques for analyzing genome architecture have often been impractical. Many established chromosome-conformation methods require millions of cells, forcing scientists to rely on abundant blood cells or mixed cell populations that may not accurately represent disease-relevant biology.
To overcome this limitation, the researchers optimized a promoter capture Hi-C method for small numbers of ILC3s isolated from human tonsils. Hi-C-based technologies measure how frequently different regions of DNA come into contact inside the nucleus. In promoter capture Hi-C, the experiment is enriched for interactions involving gene promoters, allowing researchers to focus on the regulatory connections most directly related to gene expression. The resulting map identified long-range contacts between ILC3 promoters and distant regulatory elements throughout the genome, creating a high-resolution picture of how genes are controlled in this uncommon immune-cell population.
The analysis also demonstrated why cell type matters when interpreting genetic risk. A regulatory variant may be identical in every cell of the body, but its physical contact with gene promoters can differ depending on how the DNA is folded in a particular cell type. This means that a variant associated with disease may influence one gene in an intestinal immune cell and a different gene—or no gene at all—in a circulating blood cell. By mapping the genome specifically in ILC3s, the researchers were able to identify regulatory relationships that would likely have been invisible in broader or more abundant cell populations.
The team then combined the three-dimensional DNA maps with results from genome-wide association studies, which identify genetic variants that occur more frequently in people with a particular disease. Instead of examining each variant in isolation, the researchers used a statistical framework that considered multiple variants within the same genomic region. This approach helped connect clusters of Crohn’s disease-associated variants to the genes whose promoters they physically contact in ILC3s. More than 100 candidate genes were prioritized, including many that had not previously been linked to inflammatory bowel disease.
One unexpected candidate was CLN3, a gene best known for its role in Batten disease, a rare inherited neurodegenerative disorder. The discovery suggests that genes associated with neurological disease may also influence immune-cell behavior, although the study does not establish CLN3 as a causal gene for inflammatory bowel disease. Follow-up experiments in mouse models provided functional clues: when ILC3s were activated, expression of the mouse Cln3 gene declined. Conversely, increasing Cln3 levels reduced the activity of inflammatory genes and lowered cytokine production. These results point to a possible role for CLN3 in controlling the intensity of immune activation.
The researchers emphasize that the findings represent a mechanistic lead rather than a new treatment or a definitive explanation for Crohn’s disease. Genetic association alone cannot prove that a particular gene drives disease, and the mouse experiments will require further validation in human cells and disease models. Nevertheless, the study illustrates how combining chromatin-contact maps, genetic association data and functional experiments can move scientists beyond statistical correlations toward testable biological mechanisms. It also raises the possibility that pathways traditionally studied in neurodegeneration could intersect with immune regulation through shared cellular processes.
The new method may ultimately be useful far beyond ILC3s. Rare immune populations are increasingly recognized as important contributors to autoimmune, allergic and inflammatory diseases, yet their scarcity has limited detailed genomic investigation. A technique capable of mapping promoter interactions from small numbers of cells could allow researchers to compare genome regulation across tissues, developmental stages and disease states. As scientists apply these tools to additional cell types, hidden connections between noncoding DNA and disease-relevant genes may become easier to identify, improving the interpretation of genetic risk and potentially revealing new targets for precision medicine. The study was co-led by researchers at Cincinnati Children’s and the MRC Laboratory of Medical Sciences in London, with collaborators in the United States, the United Kingdom, Belgium and the Netherlands.
Subject of Research: Human tissue samples
Article Title: High-resolution promoter interaction analysis implicates genes involved in activation of type 3 innate lymphoid cells in immune disease risk
News Publication Date: 4-Aug-2026
Web References: https://www.nature.com/articles/s41588-026-02681-0; https://doi.org/10.1038/s41588-026-02681-0
References: Nature Genetics, DOI: 10.1038/s41588-026-02681-0
Image Credits: Cincinnati Children’s
Keywords: ILC3 cells, autoimmune disease, Crohn’s disease, inflammatory bowel disease, promoter capture Hi-C, 3D genome, genetic risk, long-range DNA interactions, CLN3, immunogenetics, human genetics
