- Miniaturized Capture Hi-C was developed during Valeriya Malysheva's postdoctoral work at the MRC Laboratory of Medical Sciences, allowing for the mapping of long-range DNA interactions in rare immune cells.
- Researchers applied this method to map promoter interactions across the ILC3 genome, revealing connections between genetic variants and candidate target genes.
- The team combined the maps with GWAS data and tied Crohn's disease risk variants to more than 100 candidate genes in ILC3s, including CLN3.
- Follow-up experiments indicated that CLN3 influences inflammatory signaling in ILC3s, suggesting a role in immune response.
- The approach was extended to five additional autoimmune conditions, generating a catalog of ILC3-linked risk genes.
- A new study published in Nature Genetics shows how mapping these long-range contacts in rare immune cells can reveal the biological mechanisms linking genetic risk to Crohn’s disease and other autoimmune conditions.
- The analysis identified more than 100 genes in ILC3s that may be influenced by regulatory variants associated with Crohn’s disease, expanding the list of potential biological targets for future investigation.
- One of the most unexpected candidates was CLN3, a gene best known for its connection to Batten disease, a rare inherited neurodegenerative disorder.
- The findings do not mean that CLN3 alone causes Crohn’s disease, but they provide a mechanistic framework for understanding how non-coding variants may alter gene regulation in a cell type that participates directly in intestinal inflammation.
A new study published in *Nature Genetics* has unveiled significant insights into the genetic factors contributing to Crohn's disease by mapping the 3D genome of rare type 3 innate lymphoid cells (ILC3s).6
The research, co-led by Prof. Valeriya Malysheva, utilized a miniaturized Capture Hi-C method to analyze the gene-regulatory architecture of ILC3s, which are crucial in immune response but difficult to study due to their scarcity.1
The team identified over 100 candidate genes linked to Crohn's disease risk, with approximately half already associated with the condition. Notably, the gene CLN3, typically linked to Batten disease, emerged as a surprising candidate, suggesting a potential role in regulating inflammatory responses in ILC3s.3489
Follow-up experiments indicated that CLN3 influences the production of inflammatory signals, although it does not establish a direct causal link to Crohn's disease. The findings emphasize the importance of understanding how non-coding genetic variants can alter gene regulation in immune cells involved in intestinal inflammation.
The study's innovative approach allows for the examination of long-distance DNA interactions in rare immune cells, paving the way for future research into other autoimmune disorders. As Mikhail Spivakov, PhD, noted, “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.”
This research not only expands the understanding of Crohn's disease but also highlights the potential for discovering new therapeutic targets in the realm of autoimmune diseases.
“Using miniaturized promoter capture Hi-C, the team mapped ILC3 promoter contacts and extended the approach to five additional autoimmune conditions, generating a risk-gene catalog. Follow-up experiments showed CLN3 expression shifts after cytokine stimulation, hinting at a previously unrecognized immune role for a gene tied to Batten disease.”
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