High-resolution promoter interaction analysis in Type 3 Innate Lymphoid Cells implicates Batten Disease geneCLN3in Crohn’s Disease aetiology

Abstract

Innate lymphoid cells (ILCs) are rare tissue-resident “helper” lymphocytes that do not express diversified antigen receptors. Type 3 ILCs (ILC3s) are an important class of these cells enriched in the respiratory and intestinal mucosa, where they regulate inflammation and mucosal homeostasis. To gain insight into the cis-regulatory circuitries underlying ILC3 function, we used high-resolution Capture Hi-C to profile promoter-anchored chromosomal contacts in human primary ILC3s. Combining significant interaction detection with the Activity-By-Contact approach adapted to Capture Hi-C, we reveal a multitude of contacts between promoters and distal regulatory elements and obtain evidence for distinct regulatory wiring of alternative promoters. We find that promoter-interacting regions in ILC3s are enriched for genetic variants associated with multiple immune diseases. Focusing on Crohn’s disease (CD), in which ILC3s are established mediators, we used a Bayesian approach that incorporates multivariate fine-mapping to link CD-associated genetic variants with putative target genes. We identify known and previously unimplicated genes in conferring genetic risk of CD through activity in ILC3s. This includes the CLN3gene that is mutated in the neurodegenerative disorder Batten disease. UsingCln3mutant mice, we show thatCLN3is a putative negative regulator of IL-17 production in an inflammatory subset of ILC3s. This finding suggests a functional role forCLN3in ILC3 biology, with mechanistic implications for both Crohn’s and Batten diseases.