Low-Input 3D Genome Maps Tie ILC3 Regulatory DNA to Crohn’s Risk

Overview

• A Nature Genetics paper published August 4 reports a low-input Promoter Capture Hi‑C method that maps three-dimensional promoter contacts in rare human type 3 innate lymphoid cells (ILC3s).
• The team combined those ILC3 3D maps with GWAS using a Bayesian tool, multiCOGS, to assign noncoding Crohn’s disease risk variants to more than 100 candidate target genes.
• Among the prioritized genes was CLN3, a surprising hit best known for Batten disease, which the authors say suggests unexpected links between immune regulation and neurodevelopmental pathways.
• Mouse ILC3‑like follow-up experiments showed Cln3 falls with activation and that raising Cln3 levels reduced inflammatory gene programs and cytokine output, but the study does not establish CLN3 as a causal Crohn’s gene.
• The approach was extended to five other autoimmune conditions and a CRISPR interference screen enriched for the same regulators, and the authors say the method opens a scalable path to test mechanisms in other rare disease‑relevant cells.