Saeedi, Bejan J. and Kao, Daniel J. and Kitzenberg, D.A. and Dobrinskikh, Evgenia and Schwisow, Kayla D. and Masterson, Joanne C. and Kendrick, Agnieszka A. and Kelly, Caleb J. and Bayless, A. and Kominsky, Douglas J. and Campbell, Eric L. and Kuhn, Kristine A. and Furuta, Glenn T. and Colgan, S.P. and Glover, Louise (2015) HIF-dependent regulation of claudin-1 is central to intestinal epithelial tight junction integrity. Molecular Biology of the Cell, 26 (12). pp. 2252-2262. ISSN 1059-1524

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Abstract

Intestinal epithelial cells (IECs) are exposed to profound fluctuations in oxygen tension and have evolved adaptive transcriptional responses to a low-oxygen environment. These adaptations are mediated primarily through the hypoxia-inducible factor (HIF) complex. Given the central role of the IEC in barrier function, we sought to determine whether HIF influenced epithelial tight junction (TJ) structure and function. Initial studies revealed that short hairpin RNA–mediated depletion of the HIF1β in T84 cells resulted in profound defects in barrier and nonuniform, undulating TJ morphology. Global HIF1α chromatin immunoprecipitation (ChIP) analysis identified claudin-1 (CLDN1) as a prominent HIF target gene. Analysis of HIF1β-deficient IEC revealed significantly reduced levels of CLDN1. Overexpression of CLDN1 in HIF1β-deficient cells resulted in resolution of morphological abnormalities and restoration of barrier function. ChIP and site-directed mutagenesis revealed prominent hypoxia response elements in the CLDN1 promoter region. Subsequent in vivo analysis revealed the importance of HIF-mediated CLDN1 expression during experimental colitis. These results identify a critical link between HIF and specific tight junction function, providing important insight into mechanisms of HIF-regulated epithelial homeostasis.

Item Type:	Article
Additional Information:	© 2015 Saeedi, Kao, et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Cre-ative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0). Cite as: HIF-dependent regulation of claudin-1 is central to intestinal epithelial tight junction integrity Bejan J. Saeedi, Daniel J. Kao, David A. Kitzenberg, Evgenia Dobrinskikh, Kayla D. Schwisow, Joanne C. Masterson, Agnieszka A. Kendrick, Caleb J. Kelly, Amanda J. Bayless, Douglas J. Kominsky, Eric L. Campbell, Kristine A. Kuhn, Glenn T. Furuta, Sean P. Colgan, and Louise E. Glover Molecular Biology of the Cell 2015 26:12, 2252-2262
Keywords:	HIF-dependent; regulation; claudin-1; intestinal epithelial; tight junction integrity;
Academic Unit:	Faculty of Science and Engineering > Biology
Item ID:	12486
Identification Number:	https://doi.org/10.1091/mbc.E14-07-1194
Depositing User:	Joanne Masterson
Date Deposited:	26 Feb 2020 17:05
Journal or Publication Title:	Molecular Biology of the Cell
Publisher:	American Society for Cell Biology
Refereed:	Yes
URI:	Publisher
Use Licence:	This item is available under a Creative Commons Attribution Non Commercial Share Alike Licence (CC BY-NC-SA). Details of this licence are available here

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