title: 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.
authors: Human Genetics Institute of New Jersey and Department of Genetics, Rutgers, the State University of New Jersey, Piscataway, New Jersey, USA.
authors: Sanjay
authors: S
authors: Chahar
authors: Human Genetics Institute of New Jersey and Department of Genetics, Rutgers, the State University of New Jersey, Piscataway, New Jersey, USA.
authors: Vishal
authors: V
authors: Gandhi
authors: Department of Biological Sciences, Rutgers, the State University of New Jersey, Newark, New Jersey, USA.
authors: Shiyan
authors: S
authors: Yu
authors: Department of Genetics, Norris Cotton Cancer Center, Dartmouth Medical School, Lebanon, New Hampshire, USA.
authors: Kinjal
authors: K
authors: Desai
authors: The Princess Margaret Cancer Centre-University Health Network, Toronto, ON, Canada.
authors: Richard
authors: R
authors: Cowper-Sal-lari
authors: Human Genetics Institute of New Jersey and Department of Genetics, Rutgers, the State University of New Jersey, Piscataway, New Jersey, USA.
authors: Yona
authors: Y
authors: Kim
authors: Human Genetics Institute of New Jersey and Department of Genetics, Rutgers, the State University of New Jersey, Piscataway, New Jersey, USA.
authors: Ansu O
authors: AO
authors: Perekatt
authors: Human Genetics Institute of New Jersey and Department of Genetics, Rutgers, the State University of New Jersey, Piscataway, New Jersey, USA.
authors: Namit
authors: N
authors: Kumar
authors: Human Genetics Institute of New Jersey and Department of Genetics, Rutgers, the State University of New Jersey, Piscataway, New Jersey, USA.
authors: Joshua K
authors: JK
authors: Thackray
authors: Human Genetics Institute of New Jersey and Department of Genetics, Rutgers, the State University of New Jersey, Piscataway, New Jersey, USA.
authors: Anthony
authors: A
authors: Musolf
authors: Human Genetics Institute of New Jersey and Department of Genetics, Rutgers, the State University of New Jersey, Piscataway, New Jersey, USA.
authors: Nikhil
authors: N
authors: Kumar
authors: Human Genetics Institute of New Jersey and Department of Genetics, Rutgers, the State University of New Jersey, Piscataway, New Jersey, USA.
authors: A
authors: A
authors: Hoffman
authors: Human Genetics Institute of New Jersey and Department of Genetics, Rutgers, the State University of New Jersey, Piscataway, New Jersey, USA.
authors: Douglas
authors: D
authors: Londono
authors: Human Genetics Institute of New Jersey and Department of Genetics, Rutgers, the State University of New Jersey, Piscataway, New Jersey, USA.
authors: Berta N
authors: BN
authors: Vazquez
authors: Human Genetics Institute of New Jersey and Department of Genetics, Rutgers, the State University of New Jersey, Piscataway, New Jersey, USA.
authors: Lourdes
authors: L
authors: Serrano
authors: Department of Translational Medicine, Takeda Pharmaceuticals International, Inc., Cambridge, Massachusetts, USA.
authors: Hyunjin
authors: H
authors: Shin
authors: 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.
authors: Mathieu
authors: M
authors: Lupien
authors: 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.
authors: Nan
authors: N
authors: Gao
authors: 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.
authors: Michael P
authors: MP
authors: Verzi
mesh_terms: D000818:Animals; D001665:Binding Sites / Q000235:genetics; D018938:Caco-2 Cells; D002843:Chromatin / Q000235:genetics* / Q000378:metabolism*; D003092:Colitis / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D016264:Dextran Sulfate / Q000633:toxicity; D004195:Disease Models, Animal; D044127:Epigenesis, Genetic; D005260:Female; D055786:Gene Knockout Techniques; D053263:Gene Regulatory Networks; D020022:Genetic Predisposition to Disease; D051557:Hepatocyte Nuclear Factor 4 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000235:genetics / Q000378:metabolism; D007413:Intestinal Mucosa / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D050436:Regulatory Elements, Transcriptional
chemical_list: D002843:Chromatin; C496592:HNF4A protein, human; D051557:Hepatocyte Nuclear Factor 4; C496593:Hnf4a protein, mouse; D016264:Dextran Sulfate