3D DNA mapping connects Crohn's disease risk variants to genes

Profiling DNA interactions in a rare immune cell type provides a route from disease-associated variants to candidate genes in Crohn's disease.

Collaborative work by researchers in the UK, Belgium and the USA has advanced the study of gene regulation in a rare immune cell type – type 3 innate lymphoid cells (ILC3s). By exploring genetic variants already associated with Crohn's disease, the researchers used 3D mapping to link these variants to genes potentially involved in the immune-related condition.

'This work opens the door to studying long-distance DNA interactions in rare immune cells,' said Dr Stephen Waggoner from the Centre for Autoimmune Genomics and Etiology in Cincinnati, Ohio, and a senior author on the study. 'Until now, most methods required millions of cells, which limited what we could learn from the cell types most relevant to disease.'

DNA folds into a complex 3D structure within cells, like a ball of wool. This folding can influence which genes are switched on or off by bringing pieces of DNA together that regulate one another. In work published in Nature Genetics, the authors systematically mapped interactions between regions of DNA in ILC3 cells isolated from human tonsils. The authors combined this 3D genome map with genetic data to identify genes potentially regulated by variants associated with Crohn's disease.

'The patterns of genome folding differ across cell types, so it is important to study the 3D connections between variants and the genes they control in the cells that are relevant for the disease,' said co-author Dr Mikhail Spivakov, head of the functional gene control research group at the MRC Laboratory of Medical Sciences in London.

Crohn's disease is a chronic inflammatory bowel disease thought to be caused by genetic and environmental factors, but the disease mechanism is not well understood. Understanding the genetic factors could help researchers identify potential targets for treatment. Given the role of the immune system in Crohn's disease, capturing regulatory information in immune cells is likely relevant to how the disease develops. However, disease-associated variants may also mediate their effect in other non-immune cell types beyond the scope of this work.

The study focused on the candidate gene CLN3, which was selectively prioritised as a Crohn's disease risk gene in ILC3s but not CD4+ T cells. Experimental manipulation of CLN3 expression in a mouse ILC3-like cell-line model altered the cells' response to stimulation, including cytokine secretion, although further experimental work is needed to establish how CLN3 may contribute to Crohn's disease. This work adds to a growing list of candidate genes and regulatory variants that may help explain inflammatory bowel disease risk (see BioNews 1158 and 1242).