Epigenetic control of intestinal barrier function and inflammation in zebrafish.

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Marjoram, L; Alvers, A; Deerhake, ME; Bagwell, J; Mankiewicz, J; Cocchiaro, JL; Beerman, RW; Willer, J; Sumigray, KD; Katsanis, N; Tobin, DM; Rawls, JF; Goll, MG; Bagnat, M

Published Date

  • March 3, 2015

Published In

Volume / Issue

  • 112 / 9

Start / End Page

  • 2770 - 2775

PubMed ID

  • 25730872

Pubmed Central ID

  • PMC4352795

Electronic International Standard Serial Number (EISSN)

  • 1091-6490

Digital Object Identifier (DOI)

  • 10.1073/pnas.1424089112


  • eng

Conference Location

  • United States