Tight junction CLDN2 gene is a direct target of the Vitamin D receptor

Yong Guo Zhang, Shaoping Wu, Rong Lu, David Zhou, Jingsong Zhou, Geert Carmeliet, Elaine Petrof, Erika C. Claud, Jun Sun

Research output: Contribution to journalArticlepeer-review

101 Scopus citations

Abstract

The breakdown of the intestinal barrier is a common manifestation of many diseases. Recent evidence suggests that vitamin D and its receptor VDR may regulate intestinal barrier function. Claudin-2 is a tight junction protein that mediates paracellular water transport in intestinal epithelia, rendering them "leaky". Using whole body VDR -/- mice, intestinal epithelial VDR conditional knockout (VDR δIEC) mice, and cultured human intestinal epithelial cells, we demonstrate here that the CLDN2 gene is a direct target of the transcription factor VDR. The Caudal-Related Homeobox (Cdx) protein family is a group of the transcription factor proteins which bind to DNA to regulate the expression of genes. Our data showed that VDR-enhances Claudin-2 promoter activity in a Cdx1 binding site-dependent manner. We further identify a functional vitamin D response element (VDRE) 5′,-AGATAACAAAGGTCA-3′, in the Cdx1 site of the Claudin-2 promoter. It is a VDRE required for the regulation of Claudin-2 by vitamin D. Absence of VDR decreased Claudin-2 expression by abolishing VDR/promoter binding. In vivo, VDR deletion in intestinal epithelial cells led to significant decreased Claudin-2 in VDR -/- and VDR δIEC mice. The current study reveals an important and novel mechanism for VDR by regulation of epithelial barriers.

Original languageEnglish (US)
Article number10642
JournalScientific reports
Volume5
DOIs
StatePublished - Jul 27 2015

Bibliographical note

Funding Information:
We want to thank Dr. Takuya Suzuki from Hiroshima University, Japan for generously providing the Claudin-2 reporter plasmids. This work was supported by Brian Piccolo Cancer Award and Swim Across America Cancer Research Award to JS.

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