Scientists Discover Inflammation-Driving Gene Linked to IBD

Scientists Discover Inflammation-Driving Gene Linked to IBD

A research team at Duke University Medical Center led by Michel Bagnat identified a gene called uhrf1 that regulates tumor necrosis factor (TNF) levels in the gut. The study entitled, “Epigenetic control of intestinal barrier function and inflammation in zebrafish” was published online in Proceedings of the National Academy of Sciences on February 16, 2015.

Inflammatory bowel diseases (IBD) are a group of chronic inflammatory conditions of the colon and small intestine including Crohn’s disease and ulcerative colitis. IBD affects over 1.6 million Americans and can be triggered by various factors such as genetic variation, intestinal microbes, overactive immunity, and environmental exposures.

TNF is a mediator of inflammation and its levels are elevated in the serum, mucosa and stool of IBD patients. TNF contributes to the destruction of the barrier formed by the intestinal epithelium that protects the body from microbes and other proinflammatory stimuli. Drugs targeting TNF, such as the monoclonal anti-TNF antibody, are a highly efficacious IBD therapy. However, what triggers an increase in TNF levels in the gut, or how this leads to the onset of disease remains to be fully understood.

Zebrafish in IBDIn this study, the authors used Zebrafish as a model organism to identify mutations that increase TNF levels. In their model, Zebrafish emits fluorescence wherever the TNF gene is “turned on.” Because these small aquarium fish are transparent as embryos, fluorescence and any defects in the gut are easily visualized. Using this model, they found out that loss of the epigenetic regulator ubiquitin-like protein containing PHD and RING finger domains 1 (uhrf1) leads to induction of tnf gene expression in intestinal epithelial cells (IECs), inflaming and damaging the digestive tract. uhrf1 is involved in an epigenetic process known as DNA methylation: whether a particular gene is turned “off” or “on” in a given cell is determined by the presence or absence of specific chemical tags or methyl groups—methylation—attached to the DNA.

Uhrf1 normally acts to turn off genes that produce TNF, but when that repression is lost, those genes get turned on and TNF is manufactured and released. “You can think about it in terms of a car parked in a driveway. If you get rid of the handbrake, the car is going to start rolling,” said Bagnat in a press release.

“Our findings provide a new take on how inflammatory bowel diseases can emerge and develop,” said Dr. Bagnat, an assistant professor of cell biology at Duke University School of Medicine. “We already knew that genetic susceptibility could play a part, but we’ve found that it is not just the immune genes themselves, but also the regulation of those genes (through epigenetics), that can cause problems.”

If similar methylation defects are observed in humans, this study’s findings could provide targets for new diagnostics or therapeutics for the disease.

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