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Molecular Determinants of NOTCH4 Transcription in Vascular Endothelium

Jing Wu,^1, Fumiko Iwata,^2, Jeffrey A. Grass,¹ Cameron S. Osborne,³ Laura Elnitski,⁴ Peter Fraser,³ Osamu Ohneda,² Masayuki Yamamoto,² and Emery H. Bresnick^1*

Molecular and Cellular Pharmacology Program, Department of Pharmacology, University of Wisconsin Medical School, Madison, Wisconsin,¹ Graduate School of Comprehensive Human Science, Center for Tsukuba Advanced Research Alliance and ERATO Environmental Response Project, University of Tsukuba, Tsukuba, Japan,² Laboratory of Chromatin and Gene Expression, The Babraham Institute, Cambridge, United Kingdom,³ Department of Biochemistry, Pennsylvania State University, University Park, Pennsylvania⁴

Received 27 August 2004/ Returned for modification 27 October 2004/ Accepted 5 November 2004

The process whereby the primitive vascular network develops into the mature vasculature, known as angiogenic vascular remodeling, is controlled by the Notch signaling pathway. Of the two mammalian Notch receptors expressed in vascular endothelium, Notch1 is broadly expressed in diverse cell types, whereas Notch4 is preferentially expressed in endothelial cells. As mechanisms that confer Notch4 expression were unknown, we investigated how NOTCH4 transcription is regulated in human endothelial cells and in transgenic mice. The NOTCH4 promoter and the 5' portion of NOTCH4 assembled into an endothelial cell-specific histone modification pattern. Analysis of NOTCH4 primary transcripts in human umbilical vein endothelial cells by RNA fluorescence in situ hybridization revealed that 36% of the cells transcribed one or both NOTCH4 alleles. The NOTCH4 promoter was sufficient to confer endothelial cell-specific transcription in transfection assays, but intron 1 or upstream sequences were required for expression in the vasculature of transgenic mouse embryos. Cell-type-specific activator protein 1 (AP-1) complexes occupied NOTCH4 chromatin and conferred endothelial cell-specific transcription. Vascular angiogenic factors activated AP-1 and reprogrammed the endogenous NOTCH4 gene in HeLa cells from a repressed to a transcriptionally active state. These results reveal an AP-1-Notch4 pathway, which we propose to be crucial for transducing angiogenic signals and to be deregulated upon aberrant signal transduction in cancer.

J.W. and F.I. contributed equally.

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