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Mol Cell Biol. 2014 Sep;34(17):3291-304. doi: 10.1128/MCB.00349-14. Epub 2014 Jun 30.

Chromatin profiling reveals regulatory network shifts and a protective role for hepatocyte nuclear factor 4α during colitis.

Author information

1
Human Genetics Institute of New Jersey and Department of Genetics, Rutgers, the State University of New Jersey, Piscataway, New Jersey, USA.
2
Department of Biological Sciences, Rutgers, the State University of New Jersey, Newark, New Jersey, USA.
3
Department of Genetics, Norris Cotton Cancer Center, Dartmouth Medical School, Lebanon, New Hampshire, USA.
4
The Princess Margaret Cancer Centre-University Health Network, Toronto, ON, Canada.
5
Department of Translational Medicine, Takeda Pharmaceuticals International, Inc., Cambridge, Massachusetts, USA.
6
The Princess Margaret Cancer Centre-University Health Network, Toronto, ON, Canada Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada Ontario Institute for Cancer Research, Toronto, ON, Canada.
7
Department of Biological Sciences, Rutgers, the State University of New Jersey, Newark, New Jersey, USA Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey, USA.
8
Human Genetics Institute of New Jersey and Department of Genetics, Rutgers, the State University of New Jersey, Piscataway, New Jersey, USA Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey, USA verzi@biology.rutgers.edu.

Abstract

Transcriptional regulatory mechanisms likely contribute to the etiology of inflammatory bowel disease (IBD), as genetic variants associated with the disease are disproportionately found at regulatory elements. However, the transcription factors regulating colonic inflammation are unclear. To identify these transcription factors, we mapped epigenomic changes in the colonic epithelium upon inflammation. Epigenetic marks at transcriptional regulatory elements responded dynamically to inflammation and indicated a shift in epithelial transcriptional factor networks. Active enhancer chromatin structure at regulatory regions bound by the transcription factor hepatocyte nuclear factor 4α (HNF4A) was reduced during colitis. In agreement, upon an inflammatory stimulus, HNF4A was downregulated and showed a reduced ability to bind chromatin. Genetic variants that confer a predisposition to IBD map to HNF4A binding sites in the human colon cell line CaCo2, suggesting impaired HNF4A binding could underlie genetic susceptibility to IBD. Despite reduced HNF4A binding during inflammation, a temporal knockout model revealed HNF4A still actively protects against inflammatory phenotypes and promotes immune regulatory gene expression in the inflamed colonic epithelium. These findings highlight the potential for HNF4A agonists as IBD therapeutics.

PMID:
24980432
PMCID:
PMC4135557
DOI:
10.1128/MCB.00349-14
[Indexed for MEDLINE]
Free PMC Article

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