TY - JOUR
T1 - Chromatin profiling reveals regulatory network shifts and a protective role for hepatocyte nuclear factor 4α during colitis
AU - Chahar, Sanjay
AU - Gandhi, Vishal
AU - Yu, Shiyan
AU - Desai, Kinjal
AU - Cowper-Sallari, Richard
AU - Kim, Yona
AU - Perekatt, Ansu O.
AU - Kumar, Namit
AU - Thackray, Joshua K.
AU - Musolf, Anthony
AU - Kumar, Nikhil
AU - Hoffman, A.
AU - Londono, Douglas
AU - Vazquez, Berta N.
AU - Serrano, Lourdes
AU - Shin, Hyunjin
AU - Lupien, Mathieu
AU - Gao, Nan
AU - Verzi, Michael P.
N1 - Publisher Copyright:
© 2014, American Society for Microbiology. All Rights Reserved.
PY - 2014
Y1 - 2014
N2 - 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.
AB - 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.
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U2 - 10.1128/MCB.00349-14
DO - 10.1128/MCB.00349-14
M3 - Article
C2 - 24980432
AN - SCOPUS:84925581406
SN - 0270-7306
VL - 34
SP - 3291
EP - 3304
JO - Molecular and Cellular Biology
JF - Molecular and Cellular Biology
IS - 17
ER -