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J. Biol. Chem., Vol. 280, Issue 26, 24824-24838, July 1, 2005

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The Expression of Endothelial Nitric-oxide Synthase Is Controlled by a Cell-specific Histone Code^*

Jason E. Fish, Charles C. Matouk¶, Alisa Rachlis¶, Steven Lin¶, Sharon C. Tai¶, Cheryl D'Abreo¶, and Philip A. Marsden, Recipient of a Career Investigator Award from the Heart and Stroke Foundation of Canada and supported by Canadian Institutes of Health Research Grant CIHR MOP 36381¶||

From the Department of Medical Biophysics and the ^¶Renal Division and Department of Medicine, St. Michael's Hospital and University of Toronto, Toronto, Ontario M5S 1A8, Canada

Expression of endothelial nitric-oxide synthase (eNOS) mRNA is highly restricted to the endothelial cell layer of medium to large sized arterial blood vessels. Here we assessed the chromatin environment of the eNOS gene in expressing and nonexpressing cell types. Within endothelial cells, but not a variety of nonendothelial cells, the nucleosomes that encompassed the eNOS core promoter and proximal downstream coding regions were highly enriched in acetylated histones H3 and H4 and methylated lysine 4 of histone H3. This differentially modified chromatin domain was selectively associated with functionally competent RNA polymerase II complexes. Endothelial cells were particularly enriched in acetylated histone H3 lysine 9, histone H4 lysine 12, and di- and tri-methylated lysine 4 of histone H3 at the core promoter. Histone modifications at this region, which we have previously demonstrated to exhibit cell-specific DNA methylation, were functionally relevant to eNOS expression. Inhibition of histone deacetylase activity by trichostatin A increased acetylation of histones H3 and H4 at the eNOS proximal promoter in nonexpressing cell types and led to increased steady-state eNOS mRNA transcript levels. H3 lysine 4 methylation was also essential for eNOS expression, since treatment of endothelial cells with methylthioadenosine, a known lysine 4 methylation inhibitor, decreased eNOS RNA levels, H3 lysine 4 methylation, and RNA polymerase II loading at the eNOS proximal promoter. Importantly, methylthioadenosine also prevented the trichostatin A-mediated increase in eNOS mRNA transcript levels in nonendothelial cells. Taken together, these findings provide strong evidence that the endothelial cell-specific expression of eNOS is controlled by cell-specific histone modifications.

Received for publication, February 24, 2005 , and in revised form, May 3, 2005.

^* The Laser Capture Microdissection Facility is supported by a Heart and Stroke Foundation of Canada group grant. 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.

Recipient of an NSERC Canada Graduate Scholarship.

^|| To whom correspondence should be addressed: Rm. 7358, Medical Sciences Bldg., 1 King's College Circle, University of Toronto, Toronto, Ontario M5S 1A8, Canada. Tel.: 416-978-2441; Fax: 416-978-8765; E-mail: p.marsden{at}utoronto.ca.

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