title: Claudin-based barrier differentiation in the colonic epithelial crypt niche involves Hopx/Klf4 and Tcf7l2/Hnf4-α cascades.
abstract: Colonic enterocytes form a rapidly renewing epithelium and barrier to luminal antigens. During renewal, coordinated expression of the claudin family of genes is vital to maintain the epithelial barrier. Disruption of this process contributes to barrier compromise and mucosal inflammatory diseases. However, little is known about the regulation of this critical aspect of epithelial cell differentiation. In order to identify claudin regulatory factors we utilized high-throughput gene microarrays and correlation analyses. We identified complex expression gradients for the transcription factors Hopx, Hnf4a, Klf4 and Tcf7l2, as well as 12 claudins, during differentiation. In vitro confirmatory methods identified 2 pathways that stimulate claudin expression; Hopx/Klf4 activation of Cldn4, 7 and 15, and Tcf7l2/Hnf4a up-regulation of Cldn23. Chromatin immunoprecipitation confirmed a Tcf7l2/Hnf4a/Claudin23 cascade. Furthermore, Hnf4a conditional knockout mice fail to induce Cldn23 during colonocyte differentiation. In conclusion, we report a comprehensive screen of colonic claudin gene expression and discover spatiotemporal Hopx/Klf4 and Tcf7l2/Hnf4a signaling as stimulators of colonic epithelial barrier differentiation.
authors: Department of Pathology and Laboratory Medicine, Emory University School of Medicine , Atlanta, GA, USA.
authors: Loukia N
authors: LN
authors: Lili
authors: Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA; Institute of Biophysics, Biological Research Center, Szeged, Hungary.
authors: Attila E
authors: AE
authors: Farkas
authors: Department of Pathology and Laboratory Medicine, Emory University School of Medicine , Atlanta, GA, USA.
authors: Christian
authors: C
authors: Gerner-Smidt
authors: BioRad Labs , Hercules, CA, USA.
authors: Christian E
authors: CE
authors: Overgaard
authors: Department of Pathology and Laboratory Medicine, Emory University School of Medicine , Atlanta, GA, USA.
authors: Carlos S
authors: CS
authors: Moreno
authors: Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA; Department of Pathology, University of Michigan, Ann Arbor, MI, USA.
authors: Charles A
authors: CA
authors: Parkos
authors: Department of Pathology, University of Michigan , Ann Arbor, MI, USA.
authors: Christopher T
authors: CT
authors: Capaldo
authors: Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA; Department of Pathology, University of Michigan, Ann Arbor, MI, USA.
authors: Asma
authors: A
authors: Nusrat
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D057167:Claudins / Q000235:genetics / Q000378:metabolism*; D003106:Colon / Q000166:cytology / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D051557:Hepatocyte Nuclear Factor 4 / Q000235:genetics / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D007413:Intestinal Mucosa / Q000166:cytology / Q000378:metabolism*; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D055153:Stem Cell Niche; D058118:Transcription Factor 7-Like 2 Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D057167:Claudins; D051557:Hepatocyte Nuclear Factor 4; C496593:Hnf4a protein, mouse; C473013:Hod protein, mouse; D018398:Homeodomain Proteins; C000715468:Klf4 protein, mouse; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; C544895:Tcf7l2 protein, mouse; D058118:Transcription Factor 7-Like 2 Protein
keywords: claudins; colonic crypts; intestinal barrier