Peer-Reviewed Journal Details
Mandatory Fields
Saeedi BJ;Kao DJ;Kitzenberg DA;Dobrinskikh E;Schwisow KD;Masterson JC;Kendrick AA;Kelly CJ;Bayless AJ;Kominsky DJ;Campbell EL;Kuhn KA;Furuta GT;Colgan SP;Glover LE;
2015
June
Molecular Biology of the Cell
HIF-dependent regulation of claudin-1 is central to intestinal epithelial tight junction integrity.
Published
()
Optional Fields
26
12
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.
1939-4586
10.1091/mbc.E14-07-1194
Grant Details