High-resolution promoter interaction analysis implicates genes involved in activation of type 3 innate lymphoid cells in immune disease risk

Key Points:

• Researchers generated a comprehensive map of promoter-anchored chromosomal contacts in human innate lymphoid cells type 3 (ILC3s) using a high-resolution DpnII-based promoter capture Hi-C (PCHi-C) method, identifying over 31,000 significant promoter interactions and integrating chromatin state and gene expression data.
• They developed an adapted activity-by-contact scoring method (ABCC) for PCHi-C data to enhance detection of functional enhancer-promoter interactions, complementing existing statistical approaches and revealing distinct regulatory landscapes in ILC3s compared to CD4+ T cells.
• Comparative analyses between ILC3s and CD4+ T cells uncovered both shared and cell-type-specific promoter interactions linked to immune regulatory pathways, with disease-associated genetic variants for autoimmune and inflammatory conditions enriched in active promoter-interacting regions.
• Using multiCOGS, a Bayesian gene prioritization algorithm integrating fine-mapped GWAS data and chromosomal contacts, the study identified candidate effector genes for Crohn’s disease and other immune traits, including novel genes not previously implicated in inflammatory bowel disease, highlighting CLN3 as a regulator of ILC3 inflammatory function.
• Functional experiments in mouse ILC3-like cells showed that CLN3 modulates cytokine secretion and inflammatory gene expression, supporting its role in immune regulation, while multiCOGS analysis across six immune diseases prioritized additional genes potentially involved in ILC3-mediated inflammation.