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Chromatin Profiling Reveals Regulatory Network Shifts and a Protective Role for HNF4A during Colitis.


Chahar S, Gandhi V, Yu S, Desai K, Cowper-Sal Lari R, Kim Y, Perekatt AO, Kumar N, Thackray JK, Musolf A, Kumar N, Hoffman A, Londono D, Vazquez BN, Serrano L, Shin H, Lupien M, Gao N, Verzi MP

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 HNF4A was reduced during colitis. In agreement, upon an inflammatory stimulus HNF4A was down-regulated 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.

Tags
Bioruptor
Chromatin Shearing
ChIP-seq

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Published
June, 2014

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