Epigenetic control of intestinal barrier function and inflammation in zebrafish Journal Article


Authors: Marjoram, L.; Alvers, A.; Deerhake, M. E.; Bagwell, J.; Mankiewicz, J.; Cocchiaro, J. L.; Beerman, R. W.; Willer, J.; Sumigray, K. D.; Katsanis, N.; Tobin, D. M.; Rawls, J. F.; Goll, M. G.; Bagnat, M.
Article Title: Epigenetic control of intestinal barrier function and inflammation in zebrafish
Abstract: 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 tnfalevels 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.
Keywords: controlled study; protein expression; nonhuman; mutant protein; ubiquitin; animal cell; animal tissue; gene; cell structure; apoptosis; embryo; animal experiment; animal model; inflammation; protein; genotype; dna methylation; enteritis; intestine epithelium cell; ring finger motif; intestine function; immunocompetent cell; chronic inflammation; zebra fish; zebrafish; protein methylation; danio rerio; tumor necrosis factor; microorganism; inflammatory bowel disease; intestine epithelium; uhrf1; priority journal; article; epigenetic repression; intestine mucosa permeability; tnfa gene
Journal Title: Proceedings of the National Academy of Sciences of the United States of America
Volume: 112
Issue: 9
ISSN: 0027-8424
Publisher: National Academy of Sciences  
Date Published: 2015-03-03
Start Page: 2770
End Page: 2775
Language: English
DOI: 10.1073/pnas.1424089112
PROVIDER: scopus
PMCID: PMC4352795
PUBMED: 25730872
DOI/URL:
Notes: Export Date: 2 April 2015 -- Source: Scopus
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MSK Authors
  1. Mary Grace Goll
    6 Goll