Researchers have mapped the three-dimensional regulatory architecture of human type 3 innate lymphoid cells (ILC3s) to understand their role in immune diseases. ILC3s are resident lymphocytes that regulate inflammation and maintain barrier integrity in sites like the gut. Their dysfunction is linked to conditions such as Crohn's disease, but identifying the specific genes involved is difficult because common disease risk variants often reside in non-coding regions of the genome.
To solve this, the study team used a low-input promoter capture Hi-C protocol. This approach allowed them to identify tens of thousands of promoter-anchored chromosomal contacts in rare ILC3 samples. By integrating these interaction maps with genetic data, they developed a Bayesian gene prioritization framework called multiCOGS. This tool identifies causal effector genes by linking non-coding disease risk variants to specific gene promoters.
This analysis revealed 251 candidate genes involved in ILC3 activation and immune disease risk. Among these, the study highlights the CLN3 gene. While CLN3 is known for its role in Batten disease, this research shows that its expression is repressed during ILC3 activation. When the researchers experimentally forced higher levels of CLN3 in ILC3-like cells, they observed a reduction in inflammatory cytokine secretion, suggesting that CLN3 helps regulate the inflammatory output of these cells.
The researchers extended their findings to five other immune-related conditions, including asthma, ulcerative colitis, and celiac disease. The study demonstrates that ILC3s are not just peripheral observers in immune disorders but possess a distinct regulatory circuit that directly influences disease risk. This work provides a new map for understanding how rare cell populations contribute to complex health conditions.