# Genetic and Epigenetic Regulation of Intestinal Inflammation

> **NIH NIH R01** · DUKE UNIVERSITY · 2021 · $419,922

## Abstract

The onset of inflammatory bowel diseases (IBD), which includes Crohn's disease (CD)
and ulcerative colitis, is poorly understood, but appears to involve a combination of host
susceptibility, environmental factors and aberrant response to the luminal microbiota of
the gut. One of the hallmarks of IBD is the upregulation of the pro-inflammatory cytokine
TNF in various cell types, including immune and intestinal epithelial cells (IECs) and anti-
TNF interventions are used as IBD therapy. In spite of its clinical relevance, little is
known about the in vivo factors controlling TNF expression. In a forward zebrafish
genetic screen we found that loss of the epigenetic regulators Uhrf1 or Dnmt1 leads to
de-repression of the tnfa locus in IECs and microbe-dependent intestinal inflammation
that resembles human CD. Our proposed research addresses the central hypothesis
that defects in epigenetic regulation can trigger IBD onset in via de-repression of TNF.
We will use the zebrafish system to define transcriptional and post-transcriptional
mechanisms regulating tnfa expression and function in the intestine and how these are
influenced by microbiota. We will also investigate whether CD patients carry mutations in
DNMT1 or UHRF1 that may lead to loss of promoter methylation and de-repression of
the TNF locus. These studies are expected to yield new mechanistic insights into IBD
onset and may facilitate new approaches for IBD diagnosis and therapy.

## Key facts

- **NIH application ID:** 10126004
- **Project number:** 5R01DK113123-04
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Michel Bagnat
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $419,922
- **Award type:** 5
- **Project period:** 2018-04-02 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10126004

## Citation

> US National Institutes of Health, RePORTER application 10126004, Genetic and Epigenetic Regulation of Intestinal Inflammation (5R01DK113123-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10126004. Licensed CC0.

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