Epigenetic control of intestinal barrier function and inflammation in zebrafish

The intestinal epithelium forms a barrier protecting the organism from microbes and other proinflammatory stimuli. The integrity of this barrier and the proper response to infection requires precise regulation of powerful immune homing signals such as tumor necrosis factor (TNF). Dysregulation of TN...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2015-03, Vol.112 (9), p.2770-2775
Main Authors: Marjoram, Lindsay, Alvers, Ashley, Deerhake, M. Elizabeth, Bagwell, Jennifer, Mankiewicz, Jamie, Cocchiaro, Jordan L., Beerman, Rebecca W., Willer, Jason, Sumigray, Kaelyn D., Katsanis, Nicholas, Tobin, David M., Rawls, John F., Goll, Mary G., Bagnat, Michel
Format: Article
Language:English
Subjects:
Animals
Biological Sciences
Cells
Cytokines
Danio rerio
Digestive system
DNA Methylation
Epigenesis, Genetic - physiology
Epigenetics
Epithelial Cells - metabolism
Epithelial Cells - pathology
Gene expression
Inflammation - genetics
Inflammation - mortality
Inflammation - pathology
Inflammatory Bowel Diseases - genetics
Inflammatory Bowel Diseases - metabolism
Inflammatory Bowel Diseases - pathology
Inflammatory diseases
Intestinal Mucosa - embryology
Intestinal Mucosa - pathology
Trans-Activators - genetics
Trans-Activators - metabolism
Tumor Necrosis Factor-alpha - immunology
Tumor Necrosis Factor-alpha - metabolism
Zebrafish
Zebrafish - embryology
Zebrafish - genetics
Zebrafish Proteins - genetics
Zebrafish Proteins - metabolism
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Summary:The intestinal epithelium forms a barrier protecting the organism from microbes and other proinflammatory stimuli. The integrity of this barrier and the proper response to infection requires precise regulation of powerful immune homing signals such as tumor necrosis factor (TNF). Dysregulation of TNF leads to inflammatory bowel diseases (IBD), but the mechanism controlling the expression of this potent cytokine and the events that trigger the onset of chronic inflammation are unknown. Here, we show that loss of function of the epigenetic regulator ubiquitin-like protein containing PHD and RING finger domains 1 ( uhrf1 ) in zebrafish leads to a reduction in tnfa promoter methylation and the induction of tnfa expression in intestinal epithelial cells (IECs). The increase in IEC tnfa levels is microbe-dependent and results in IEC shedding and apoptosis, immune cell recruitment, and barrier dysfunction, consistent with chronic inflammation. Importantly, tnfa knockdown in uhrf1 mutants restores IEC morphology, reduces cell shedding, and improves barrier function. We propose that loss of epigenetic repression and TNF induction in the intestinal epithelium can lead to IBD onset. Significance Inflammatory bowel diseases (IBD), including Crohn’s disease and ulcerative colitis, are intestinal disorders of poorly understood origin and are associated with significant morbidity and mortality. A crucial factor associated with IBD onset is the presence of elevated levels of the proinflammatory cytokine tumor necrosis factor (TNF) in the intestine, signified by the use of anti-TNF therapy to treat patients with Crohn’s disease. Despite its pathogenic relevance, the mechanisms regulating TNF expression and IBD onset remain largely unknown. Here, we show that loss of epigenetic regulation results in the induction of TNF in the intestinal epithelium, leading to a loss of intestinal barrier function and inflammation. Our results suggest that mutations in genes controlling epigenetic regulators can lead to IBD onset.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1424089112