Antwerp, 4 August 2026 — The genome is often described as a linear sequence of DNA, but inside a living cell it behaves more like a densely folded, three-dimensional network. Genes can be regulated by DNA elements located far away along the chromosome, yet brought into close physical proximity by the genome’s folding pattern. A new study published in Nature Genetics shows how mapping these long-range contacts in rare immune cells can reveal the biological mechanisms linking genetic risk to Crohn’s disease and other autoimmune conditions.
The research was co-led by Prof. Valeriya Malysheva, group leader at the VIB-UAntwerp Center for Molecular Neurology, and focuses on type 3 innate lymphoid cells, or ILC3s. These specialized immune cells are found at barrier tissues including the intestine, where they help coordinate inflammation, maintain tissue integrity and support repair. Because ILC3s are relatively uncommon, however, scientists have had difficulty obtaining enough material to examine their gene-regulatory architecture using conventional genomic technologies.
That limitation is important because many disease-associated genetic variants do not alter the protein-coding sequence of a gene. Instead, they occur in regulatory regions such as enhancers, which can control gene activity from a considerable distance. Identifying the gene influenced by a regulatory variant is therefore not straightforward. The relevant DNA elements may lie thousands or even millions of DNA letters away from their target genes in the linear genome, while their physical interaction inside the nucleus can provide a direct clue to the underlying mechanism.
To overcome the problem of limited cell numbers, the researchers used miniaturized Capture Hi-C, a method developed by Malysheva during her postdoctoral work at the MRC Laboratory of Medical Sciences in the United Kingdom. Hi-C-based methods measure contacts between different regions of the genome by capturing and sequencing DNA fragments that have been close together in the nucleus. Capture Hi-C adds a targeted enrichment step, allowing investigators to examine selected genomic regions with greater sensitivity. The miniaturized version reduces the number of cells required, making high-resolution analysis possible in rare populations such as ILC3s.
The team applied the method to map promoter interactions across the ILC3 genome. Promoters are regulatory DNA regions positioned near genes and help initiate transcription, the process by which DNA instructions are copied into RNA. By determining which disease-associated regulatory regions physically contact which promoters, the researchers were able to connect genetic variants linked to Crohn’s disease risk with candidate target genes. This approach provided information that could not be obtained from genetic association studies alone, because statistical links between variants and disease do not automatically reveal the genes or cell types involved.
The analysis identified more than 100 genes in ILC3s that may be influenced by regulatory variants associated with Crohn’s disease. Approximately half had already been implicated in the disease, supporting the validity of the regulatory maps. The remaining genes had not previously been connected to Crohn’s disease, expanding the list of potential biological targets for future investigation. The findings also suggest that genetic risk may be concentrated in specific immune-cell states rather than distributed uniformly across all cell types.
One of the most unexpected candidates was CLN3, a gene best known for its connection to Batten disease, a rare inherited neurodegenerative disorder. The study’s follow-up experiments indicated that CLN3 directly affects how strongly ILC3s produce inflammatory signals. This result places the gene in an immune-regulatory context that had not been fully appreciated and highlights how disease biology can cross traditional boundaries between organ systems. A gene associated primarily with the nervous system may also influence the behavior of immune cells in the intestine.
The findings do not mean that CLN3 alone causes Crohn’s disease, nor that every genetic variant identified will produce the same effect in every person. Crohn’s disease is a complex condition shaped by many genetic factors, immune pathways, environmental influences and interactions with the gut microbiome. Rather, the study provides a mechanistic framework for understanding how non-coding variants may alter gene regulation in a cell type that participates directly in intestinal inflammation. These insights could eventually help researchers prioritize therapeutic targets or identify disease mechanisms that are missed in studies of more abundant immune cells.
More broadly, the work demonstrates the value of combining genetic data with cell-specific maps of three-dimensional DNA organization. Genome-wide association studies can identify regions associated with disease, but functional interpretation requires knowing when, where and how those regions regulate genes. By making promoter interaction analysis feasible in scarce cell populations, miniaturized Capture Hi-C offers a way to connect statistical genetic signals to cellular processes. The researchers’ results provide a detailed view of ILC3 regulation and may guide similar studies of rare immune cells involved in autoimmune disorders beyond Crohn’s disease.
Journal: Nature Genetics
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 August 2026
Web References: https://doi.org/10.1038/s41588-026-02681-0
References: https://doi.org/10.1038/s41588-026-02681-0
Keywords: Crohn’s disease, autoimmune disease, type 3 innate lymphoid cells, ILC3s, three-dimensional genome organization, Capture Hi-C, gene regulation, CLN3, immunology, genetics, inflammatory signaling
