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Proc Natl Acad Sci U S A. 2015 Mar 3;112(9):2770-5. doi: 10.1073/pnas.1424089112. Epub 2015 Feb 17.

Epigenetic control of intestinal barrier function and inflammation in zebrafish.

Author information

1
Departments of Cell Biology.
2
Developmental Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065; and.
3
Department of Biological Sciences, North Carolina State University, Raleigh, NC 27695.
4
Molecular Genetics and Microbiology and.
5
Departments of Cell Biology, Center for Human Disease Modeling, Duke University Medical Center, Durham, NC 27710;
6
Departments of Cell Biology, Dermatology, and.
7
Departments of Cell Biology, m.bagnat@cellbio.duke.edu.

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 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.

KEYWORDS:

DNA methylation; Uhrf1; inflammation; tumor necrosis factor; zebrafish

Comment in

PMID:
25730872
PMCID:
PMC4352795
DOI:
10.1073/pnas.1424089112
[Indexed for MEDLINE]
Free PMC Article

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