Chromatin Profiling Reveals Regulatory Network Shifts and a Protective Role for Hepatocyte Nuclear Factor 4α during Colitis

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.

SUPPLEMENTAL MATERIAL

Supplemental material for this article may be found at http://dx.doi.org/10.1128/MCB.00349-14.

ACKNOWLEDGMENTS

We thank Sylvie Robine for sharing Vill-Cre^ERT2 mice, Jay Tishfield for support in quantitative image analysis, and Kiron Das for helpful discussions.

The study was supported by grants from the Human Genetics Institute of New Jersey (M.P.V.), National Institutes of Health grants K01DK088868 (M.P.V.) and R01CA155004 (M.L.), and the Princess Margaret Cancer Foundation (M.L.). M.L. holds a young investigator award from the Ontario Institute for Cancer Research and a new investigator salary award from the Canadian Institute of Health Research.

We declare no conflicts of interest.