New approach opens rare immune cells to genetic risk research
Much of how genetic risk leads to disease has remained hidden. In many cases, genetic variants linked to disease do not act on nearby genes along the chromosome. Instead, they influence genes located far away along the DNA sequence. This happens because DNA is folded inside the cell, bringing distant regions into physical contact.
A new genomic approach has enabled researchers to uncover hidden connections between distant DNA regions and genes in type 3 innate lymphoid cells (ILC3s), immune cells that play crucial roles in disease. The study, co-led by scientists at Cincinnati Children's Hospital and the MRC Laboratory of Medical Sciences in London, used an optimized promoter capture Hi-C method to examine DNA folding and gene promoter interactions in ILC3s.
This technique allowed the researchers to study these rare cells with fewer cells than previously required, overcoming a major barrier in understanding genetic risk factors. The findings reveal that regulatory DNA elements often influence gene activity over long distances, and that promoter contacts can differ between cell types.
By linking this 3D interaction map to genome-wide association studies (GWAS), the researchers identified over 100 candidate genes linked to Crohn's disease risk, including CLN3, which has not been previously associated with immune system-driven diseases. Follow-up experiments in mouse models showed that increasing CLN3 levels reduced inflammatory gene activity and cytokine production.
These discoveries highlight the potential for understanding the intersection of immune regulation and neurodevelopmental disease pathways, opening new avenues for exploring rare cell types and their roles in disease.
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