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Epigenetic control of intestinal barrier function and inflammation in zebrafish.

Publication ,  Journal Article
Marjoram, L; Alvers, A; Deerhake, ME; Bagwell, J; Mankiewicz, J; Cocchiaro, JL; Beerman, RW; Willer, J; Sumigray, KD; Katsanis, N; Tobin, DM ...
Published in: Proc Natl Acad Sci U S A
March 3, 2015

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.

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Published In

Proc Natl Acad Sci U S A

DOI

EISSN

1091-6490

Publication Date

March 3, 2015

Volume

112

Issue

9

Start / End Page

2770 / 2775

Location

United States

Related Subject Headings

  • Zebrafish Proteins
  • Zebrafish
  • Tumor Necrosis Factor-alpha
  • Trans-Activators
  • Intestinal Mucosa
  • Inflammatory Bowel Diseases
  • Inflammation
  • Epithelial Cells
  • Epigenesis, Genetic
  • DNA Methylation
 

Citation

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Marjoram, L., Alvers, A., Deerhake, M. E., Bagwell, J., Mankiewicz, J., Cocchiaro, J. L., … Bagnat, M. (2015). Epigenetic control of intestinal barrier function and inflammation in zebrafish. Proc Natl Acad Sci U S A, 112(9), 2770–2775. https://doi.org/10.1073/pnas.1424089112
Marjoram, Lindsay, Ashley Alvers, M Elizabeth Deerhake, Jennifer Bagwell, Jamie Mankiewicz, Jordan L. Cocchiaro, Rebecca W. Beerman, et al. “Epigenetic control of intestinal barrier function and inflammation in zebrafish.Proc Natl Acad Sci U S A 112, no. 9 (March 3, 2015): 2770–75. https://doi.org/10.1073/pnas.1424089112.
Marjoram L, Alvers A, Deerhake ME, Bagwell J, Mankiewicz J, Cocchiaro JL, et al. Epigenetic control of intestinal barrier function and inflammation in zebrafish. Proc Natl Acad Sci U S A. 2015 Mar 3;112(9):2770–5.
Marjoram, Lindsay, et al. “Epigenetic control of intestinal barrier function and inflammation in zebrafish.Proc Natl Acad Sci U S A, vol. 112, no. 9, Mar. 2015, pp. 2770–75. Pubmed, doi:10.1073/pnas.1424089112.
Marjoram L, Alvers A, Deerhake ME, Bagwell J, Mankiewicz J, Cocchiaro JL, Beerman RW, Willer J, Sumigray KD, Katsanis N, Tobin DM, Rawls JF, Goll MG, Bagnat M. Epigenetic control of intestinal barrier function and inflammation in zebrafish. Proc Natl Acad Sci U S A. 2015 Mar 3;112(9):2770–2775.
Journal cover image

Published In

Proc Natl Acad Sci U S A

DOI

EISSN

1091-6490

Publication Date

March 3, 2015

Volume

112

Issue

9

Start / End Page

2770 / 2775

Location

United States

Related Subject Headings

  • Zebrafish Proteins
  • Zebrafish
  • Tumor Necrosis Factor-alpha
  • Trans-Activators
  • Intestinal Mucosa
  • Inflammatory Bowel Diseases
  • Inflammation
  • Epithelial Cells
  • Epigenesis, Genetic
  • DNA Methylation