title: HNF4α regulates claudin-7 protein expression during intestinal epithelial differentiation.
abstract: The intestinal epithelium is a dynamic barrier that maintains the distinct environments of intestinal tissue and lumen. Epithelial barrier function is defined principally by tight junctions, which, in turn, depend on the regulated expression of claudin family proteins. Claudins are expressed differentially during intestinal epithelial cell (IEC) differentiation. However, regulatory mechanisms governing claudin expression during epithelial differentiation are incompletely understood. We investigated the molecular mechanisms regulating claudin-7 during IEC differentiation. Claudin-7 expression is increased as epithelial cells differentiate along the intestinal crypt-luminal axis. By using model IECs we observed increased claudin-7 mRNA and nascent heteronuclear RNA levels during differentiation. A screen for potential regulators of the CLDN7 gene during IEC differentiation was performed using a transcription factor/DNA binding array, CLDN7 luciferase reporters, and in silico promoter analysis. We identified hepatocyte nuclear factor 4α as a regulatory factor that bound endogenous CLDN7 promoter in differentiating IECs and stimulated CLDN7 promoter activity. These findings support a role of hepatocyte nuclear factor 4α in controlling claudin-7 expression during IEC differentiation.
authors.affiliation: Epithelial Pathobiology and Mucosal Inflammation Research Unit, Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia.
authors.forename: Attila E
authors.initials: AE
authors.lastname: Farkas
authors.affiliation: Epithelial Pathobiology and Mucosal Inflammation Research Unit, Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia.
authors.forename: Roland S
authors.initials: RS
authors.lastname: Hilgarth
authors.affiliation: Epithelial Pathobiology and Mucosal Inflammation Research Unit, Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia.
authors.forename: Christopher T
authors.initials: CT
authors.lastname: Capaldo
authors.affiliation: Epithelial Pathobiology and Mucosal Inflammation Research Unit, Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia.
authors.forename: Christian
authors.initials: C
authors.lastname: Gerner-Smidt
authors.affiliation: Division of Pulmonary, Allergy and Critical Care Medicine, Department of Cell Biology, Emory University School of Medicine, Atlanta, Georgia.
authors.forename: Doris R
authors.initials: DR
authors.lastname: Powell
authors.affiliation: Division of Pulmonary, Allergy and Critical Care Medicine, Department of Cell Biology, Emory University School of Medicine, Atlanta, Georgia.
authors.forename: Paula M
authors.initials: PM
authors.lastname: Vertino
authors.affiliation: Department of Radiation Oncology and the Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia.
authors.forename: Michael
authors.initials: M
authors.lastname: Koval
authors.affiliation: Epithelial Pathobiology and Mucosal Inflammation Research Unit, Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia; Department of Pathology, University of Michigan, Ann Arbor, Michigan.
authors.forename: Charles A
authors.initials: CA
authors.lastname: Parkos
authors.affiliation: Epithelial Pathobiology and Mucosal Inflammation Research Unit, Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia; Department of Pathology, University of Michigan, Ann Arbor, Michigan. Electronic address: anusrat@med.umich.edu.
authors.forename: Asma
authors.initials: A
authors.lastname: Nusrat
mesh_terms: D018938:Caco-2 Cells; D002454:Cell Differentiation / Q000235:genetics*; D057167:Claudins / Q000235:genetics / Q000378:metabolism*; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism*; D005786:Gene Expression Regulation; D019073:HT29 Cells; D051557:Hepatocyte Nuclear Factor 4 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007413:Intestinal Mucosa / Q000166:cytology / Q000378:metabolism*; D011401:Promoter Regions, Genetic
chemical_list: C473255:CLDN7 protein, human; D057167:Claudins; C496592:HNF4A protein, human; D051557:Hepatocyte Nuclear Factor 4