Genome Mapping Reveals Autoimmune Disease Risk Genes in Innate Lymphoid Cells

A new study published in Nature Genetics suggests that looking beyond the nearest gene may be essential for understanding how immune disease risk variants act in rare immune cells.

The paper, “High-resolution promoter interaction analysis implicates genes involved in activation of type 3 innate lymphoid cells in immune disease risk,” was co-led by researchers at Cincinnati Children’s Hospital, the MRC Laboratory of Medical Sciences, Imperial College London, along with collaborators. The team mapped long-distance DNA interactions in type 3 innate lymphoid cells, or ILC3s, a rare population of tissue-resident immune cells enriched in the gut, airways, and mucosal lymphoid tissues.

ILC3s help regulate inflammation and maintain barrier integrity, but their rarity has made them difficult to study with conventional genome-organization methods. Many approaches for mapping chromosomal contacts require millions of cells, limiting their use in cell types that may be particularly relevant to disease.

“This work opens the door to studying long-distance DNA interactions in rare immune cells,” says Stephen Waggoner, PhD, scientist in the Center of Autoimmune Genomics and Etiology at Cincinnati Children’s. “Until now, most methods required millions of cells, which limited what we could learn from the cell types most relevant to disease.”

To address that limitation, the investigators used a low-input, high-resolution Promoter Capture Hi-C (PCHi-C) approach to map promoter-anchored chromosomal contacts in primary human ILC3s, alongside CD4+ T cells. They then combined those maps with genome-wide association study data using a Bayesian framework, multiCOGS, to connect Crohn’s disease risk variants with the genes they are most likely to regulate.

“While some disease risk variants act on the genes nearest to them, others do not, so if we only look at the nearest gene, we may get the underlying mechanisms wrong,” says Mikhail Spivakov, PhD, head of the Functional Gene Control Research Group at MRC Laboratory of Medical Sciences. “What is more, 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.”

Follow-up experiments in a mouse ILC3-like cell line supported a possible role for CLN3 in regulating inflammatory activity. According to the paper, CLN3 was downregulated after cytokine stimulation, while increasing CLN3 expression altered stimulation-induced transcriptional programs and cytokine secretion. The findings do not establish CLN3 as a causal gene in Crohn’s disease, but they point to a potential immune-related function for a gene more commonly discussed in the context of neurodevelopmental disease.

The researchers also extended the approach to five additional autoimmune conditions, generating a catalog of ILC3-linked risk genes. These genes were enriched for regulators of the ILC3 inflammatory response identified in a CRISPR interference screen.

The next steps appear to include clarifying how CLN3 influences immune-cell function, testing whether the pathways identified in ILC3s can help explain disease mechanisms, and applying the low-input mapping strategy to other rare cell types that have been difficult to study. “Studying genetic regulation in rare cell types allows us to move closer to mechanism, not just association, and that’s essential for making genetic findings meaningful across medicine,” says Waggoner.

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