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J. Biol. Chem., Vol. 283, Issue 5, 2741-2750, February 1, 2008

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Sequences in Intron 51 of the von Willebrand Factor Gene Target Promoter Activation to a Subset of Lung Endothelial Cells in Transgenic Mice^*

Ann M. Kleinschmidt, Marjan Nassiri, Molly S. Stitt^¶, Karla Wasserloos^¶, Simon C. Watkins^||, Bruce R. Pitt^¶, and Nadia Jahroudi¹

From the Biology Department, Allegheny College, Meadville, Pennsylvania 16335, the ^¶Department of Environmental and Occupational Health, University of Pittsburgh Graduate School of Public Health Pittsburgh, Pennsylvania 15219, the ^||Department Cell Biology and Physiology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, and the Department of Medicine, University of Alberta, Edmonton, Alberta T6G 2S2, Canada

In vivo analyses of the VWF promoter previously demonstrated that a fragment spanning sequences -487 to +247 targets promoter activation to brain vascular endothelial cells, whereas a longer fragment including 2182 bp of the 5'-flanking sequences, the first exon, and the first intron activated expression in endothelial cells of the heart and muscles as well as the brain of transgenic mice. These results suggested that additional VWF gene sequences were required for expression in other vascular endothelial cells in vivo. We have now identified a region within intron 51 of the VWF gene that is DNase I-hypersensitive (HSS) specifically in nonendothelial cells and interacts with endothelial and nonendothelial specific complexes that contain YY1. We demonstrate that β-actin is associated with YY1 specifically in the nucleus of nonendothelial cells and is a component of the nuclear protein complexes that interact with the DNase I-hypersensitive region. In vitro transfection analyses demonstrated that HSS sequences containing this YY1-binding site do not significantly affect VWF promoter activity. However, in vivo analyses demonstrated that addition of these sequences to the VWF promoter (-487 to +247) results in promoter activation in lung and brain vascular endothelial cells. These results demonstrate that the HSS sequences in intron 51 of the VWF gene contain cis-acting elements that are necessary for the VWF gene transcription in a subset of lung endothelial cells in vivo.

Received for publication, July 3, 2007 , and in revised form, November 16, 2007.

^* This work was supported by National Institutes of Health Grant HL-67729 (to N. J.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental data.

¹ To whom correspondence should be addressed: Dept. of Medicine/Nephrology, 261C-HMRC, University of Alberta, Edmonton, Alberta T6G 2S2, Canada. Fax: 780-492-6702; E-mail: nadia.jahroudi{at}ualberta.ca.

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