ZFIN ID: ZDB-PUB-150303-1
Epigenetic control of intestinal barrier function and inflammation in zebrafish
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.
Date: 2015
Source: Proceedings of the National Academy of Sciences of the United States of America   112(9): 2770-5 (Journal)
Registered Authors: Bagnat, Michel, Beerman, Rebecca, Cocchiaro, Jordan, Goll, Mary, Katsanis, Nicholas, Rawls, John F., Tobin, David, Willer, Jason
Keywords: DNA methylation, Uhrf1, inflammation, tumor necrosis factor, zebrafish
MeSH Terms:
  • Animals
  • DNA Methylation*
  • Epigenesis, Genetic/physiology*
  • Epithelial Cells/metabolism
  • Epithelial Cells/pathology
  • Inflammation/genetics
  • Inflammation/mortality
  • Inflammation/pathology
  • Inflammatory Bowel Diseases/genetics
  • Inflammatory Bowel Diseases/metabolism*
  • Inflammatory Bowel Diseases/pathology
  • Intestinal Mucosa/embryology*
  • Intestinal Mucosa/pathology
  • Trans-Activators/genetics
  • Trans-Activators/metabolism
  • Tumor Necrosis Factor-alpha/immunology
  • Tumor Necrosis Factor-alpha/metabolism
  • Zebrafish/embryology*
  • Zebrafish/genetics
  • Zebrafish Proteins/genetics
  • Zebrafish Proteins/metabolism
PubMed: 25730872 Full text @ Proc. Natl. Acad. Sci. USA
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.