3D genome mapping in rare immune cells reveals new Crohn's disease genes

A groundbreaking study co-led by professor Valeriya Malysheva has uncovered how the three-dimensional organization of DNA in rare immune cells can provide insights into the genetic risk of Crohn's disease and other autoimmune conditions. The research, published in Nature Genetics, challenges the traditional view of DNA as a linear sequence and emphasizes the significance of its spatial folding within cells.

This three-dimensional architecture is essential for gene regulation, and understanding it can help explain how disease-associated genetic variants impact cellular functions.

The study focused on a specific type of innate lymphoid cells (ILC3s), a scarce population of immune cells involved in inflammation and tissue repair in barrier tissues like the gut. Identifying the regulatory role of these cells in disease has been challenging due to their rarity. However, the researchers employed a novel method called miniaturized Capture Hi-C, developed by Malysheva during her postdoctoral work at the MRC Laboratory of Medical Sciences in the UK.

This technique enables the mapping of long-range DNA interactions in rare cell populations using significantly fewer cells compared to conventional methods.

By applying this approach to ILC3s, the team connected disease-associated genetic variants in regulatory DNA regions to the genes they most likely influence. The analysis identified over 100 genes in ILC3s that may be impacted by regulatory variants associated with Crohn's disease risk. Half of these genes were previously known to play a role in the disease, while the others had not been previously implicated.

One particularly striking finding was the involvement of the CLN3 gene, known primarily for its role in the neurodegenerative disorder Batten disease. The researchers demonstrated that CLN3 directly influences the production of inflammatory signals in ILC3s, revealing an unexpected connection between the nervous and immune systems.

This discovery highlights the power of genome-wide integrative approaches in uncovering unforeseen relationships and provides valuable insights into the genetic basis of autoimmune diseases.