PUBLICATION
Epigenetic control of intestinal barrier function and inflammation in zebrafish
- 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.
- ID
- ZDB-PUB-150303-1
- 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
Citation
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. (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):2770-5.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping