Epigenetic control of intestinal barrier function and inflammation in zebrafish

Lindsay Marjoram, Ashley Alvers, M. Elizabeth Deerhake, Jennifer Bagwell, Jamie Mankiewicz, Jordan L. Cocchiaro, Rebecca W. Beerman, Jason Willer, Kaelyn D. Sumigray, Elias Nicholas Katsanis, David M. Tobin, John F. Rawls, Mary G. Goll, Michel Bagnat*

*Corresponding author for this work

Research output: Contribution to journalArticle

72 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)2770-2775
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume112
Issue number9
DOIs
StatePublished - Mar 3 2015

Keywords

  • DNA methylation
  • Inflammation
  • Tumor necrosis factor
  • Uhrf1
  • Zebrafish

ASJC Scopus subject areas

  • General

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  • Cite this

    Marjoram, L., Alvers, A., Deerhake, M. E., Bagwell, J., Mankiewicz, J., Cocchiaro, J. L., Beerman, R. W., Willer, J., Sumigray, K. D., Katsanis, E. N., Tobin, D. M., Rawls, J. F., Goll, M. G., & Bagnat, M. (2015). Epigenetic control of intestinal barrier function and inflammation in zebrafish. Proceedings of the National Academy of Sciences of the United States of America, 112(9), 2770-2775. https://doi.org/10.1073/pnas.1424089112