Tumor necrosis factor (TNF) is a cell signaling protein that promotes immune responses in healthy individuals but, when overexpressed, causes inflammation in tissues affected by inflammatory bowel disease (IBD). Anti-TNF treatments can help to manage symptoms in patients with Crohn's disease, but little is known about what mediates TNF expression.
To pinpoint possible genetic mechanisms behind IBD symptoms, Lindsay Marjoram and colleagues at Duke University School of Medicine (Durham, NC) bred strains of mutant zebrafish with gut defects similar to those found in people with IBD (Proc. Natl. Acad. Sci. USA doi:10.1073/pnas.1424089112; published online 17 February 2015). In one of these strains with multiple IBD symptoms, Marjoram and her team identified that a mutation of the gene uhrf1 was responsible for upregulation of TNF in intestinal epithelial cells. uhrf1 is known to function in the maintenance of DNA methylation, and follow-up sequencing confirmed that the uhrf1 mutants had a marked reduction in DNA methylation at sites near the TNF promoter gene. These findings confirm the importance of TNF overexpression as an aggravating cause of IBD symptoms and, more generally, provide evidence that epigenetic mechanisms (and the failure thereof) can mediate these symptoms in zebrafish and maybe in humans as well. GDL
This is a preview of subscription content, access via your institution