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Papers In Press, published online ahead of print June 4, 2004
Medicine Dept., University of Toronto, Toronto, Ontario M5S 1A8
Corresponding Author: p.marsden{at}utoronto.ca
The basis for the endothelial cell-restricted expression of endothelial nitric oxide synthase (eNOS) is not known. While transgenic promoter/reporter mice demonstrated endothelial-specific eNOS expression, we found robust expression of episomal eNOS promoter/reporter constructs in cell types that do not express the native eNOS transcript. To explore the mechanism underlying this differential activity pattern of chromatin- versus episomal-based eNOS promoters, we examined the methylation status of 5'-regulatory sequences of the human eNOS gene. DNA methylation differed dramatically between endothelial and non-endothelial cell types, including vascular smooth muscle cells. This same cell-type specific methylation pattern was observed in vivo in endothelial and vascular smooth muscle cells of the mouse aorta at the native murine eNOS promoter. We addressed the functional consequences of methylation on eNOS transcription using transient transfection of in vitro methylated promoter/reporter constructs and found that methylated constructs exhibited a marked decrease in the synergistic action of Sp1, Sp3, and Ets1 on eNOS promoter activity. The addition of MeCP2 further reduced the transcriptional activity of methylated eNOS constructs. Importantly, chromatin immunoprecipitation demonstrated the presence of Sp1, Sp3 and Ets1 at the native eNOS promoter in endothelial cells but not in vascular smooth muscle cells. Finally, robust expression of eNOS mRNA was induced in non-endothelial cell types following inhibition of DNA methyltransferase activity with 5-azacytidine, demonstrating the importance of DNA methylation-mediated repression. This report is the first to show that promoter DNA methylation plays an important role in the cell-specific expression of a constitutively expressed gene in the vascular endothelium.
J. Biol. Chem, 10.1074/jbc.M405063200
Submitted on May 6, 2004
Revised on June 4, 2004
Accepted on June 4, 2004
The cell-specific expression of endothelial nitric oxide synthase: a role for DNA methylation
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