Who Gets Celiac Disease? The Dark Genome Has an Answer
The dark genome is largely a mystery but a new study from immunologists at Columbia University suggests it plays a key role in determining who develops celiac disease.
The study, from the lab of Sankar Ghosh, shows that a small element of the dark genome—a long noncoding strand of RNA called lnc13—appears to help shield people born with celiac genes from developing the disease. But when lnc13 is less active, gluten is more likely to trigger the immune system into attacking the intestinal lining.
“This finding helps explain a longstanding paradox in celiac disease,” says Ghosh, chair of the Department of Microbiology and Immunology and the Silverstein and Hutt Family Professor of Microbiology at Columbia University Vagelos College of Physicians and Surgeons. Celiac disease only develops in people who possess at least one of two specific immune genes, HLA-DQ2 or HLA-DQ8, but those genes are not sufficient to trigger the disease after gluten exposure.
“About a third of all people have these celiac genes, but only 1% of people become gluten-intolerant,” Ghosh says. “Our study shows that if you have one of the two celiac genes and a defective lnc13, you're more likely to develop the disease.”
New model of celiac disease
The study builds on earlier research from the Ghosh lab, which found that mutations in lnc13 were associated with celiac disease and that patients with the disease had dramatically lower levels of lnc13 in their immune cells.
In the new study, the researchers looked at the details of lnc13 activity in mice to understand how it works. They discovered that lnc13 helps restrain inflammatory immune responses and maintain tolerance to gluten in mice with a human celiac gene, while loss of lnc13 makes the immune system more likely to initiate a response to gluten.
The finding could be an essential advance that leads to better treatments for celiac disease, which is currently only controlled with a strict, gluten-free diet.
Modeling celiac with high fidelity. Without lnc13, the lower layer of intestinal cells displays hallmarks of celiac disease, expanding in reaction to gluten-induced inflammation.
“One thing that has made celiac so hard to study is the lack of a mouse model that truly resembles the human disease,” says Ghosh. “By inactivating lnc13 in mice with a human celiac gene, we can reproduce key features of the human disease—including immune activation, intestinal pathology, and reversal when gluten is removed from the diet.”
“This model, with its high level of physiological fidelity to what we see in patients, should help celiac researchers explore therapeutic strategies aimed at restoring the patient’s immune system to normal.”
Finding the right lnc
Ghosh’s team took an unusual approach to understanding lncRNA involvement in celiac by limiting the search to lncRNAs shared between humans and mice.
“Very few lncRNAs are shared, but if you look at lncRNAs that only exist in humans, you are kind of stuck,” says Ghosh. “We can’t really understand how lncRNAs work from human cells in lab dishes, we need to see their activity in a whole animal. We therefore focused on lncRNAs conserved between humans and mice, because those can be studied mechanistically in vivo.”
In unpublished research using the same approach, Ghosh’s lab has found additional lncRNAs regulating other immune disorders.
Ghosh says that a better understanding of the role of lncRNAs in human health should emerge if scientists can decipher the logic behind them. “We don’t know why we have them or what they do, but Nature must have created them for a purpose.”