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J. Biol. Chem. 285 (2): 810-826

© 2010 by The American Society for Biochemistry and Molecular Biology, Inc.

Hypoxic Repression of Endothelial Nitric-oxide Synthase Transcription Is Coupled with Eviction of Promoter Histones*Formula {diamondsuit}

Jason E. Fish{ddagger}§1, Matthew S. Yan2, Charles C. Matouk, Rosanne St. Bernard, J. J. David Ho, Anna Gavryushova, Deepak Srivastava§, , and Philip A. Marsden{ddagger}3

From the {ddagger}Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5S 1A8, Canada,
the Renal Division and Department of Medicine, St. Michael's Hospital and University of Toronto, Toronto, Ontario M5B 1W8, Canada, and
the §Gladstone Institute of Cardiovascular Disease and University of California, San Francisco, California, 94158

ABSTRACT Back to Top

Abstract: Hypoxia elicits endothelial dysfunction, in part, through reduced expression of endothelial nitric-oxide synthase (eNOS). Here we present evidence that hypoxia causes a rapid decrease in the transcription of the eNOS/NOS3 gene, accompanied by decreased acetylation and lysine 4 (histone H3) methylation of eNOS proximal promoter histones. Surprisingly, we demonstrate that histones are rapidly evicted from the eNOS proximal promoter during hypoxia. We also demonstrate endothelium-specific H2A.Z incorporation at the eNOS promoter and find that H2A.Z is also evicted by hypoxic stimulation. After longer durations of hypoxia, histones are reincorporated at the eNOS promoter, but these histones lack substantial histone acetylation. Additionally, we identify a key role for the chromatin remodeler, BRG1, in re-establishing eNOS expression following reoxygenation of hypoxic cells. We posit that post-translational histone modifications are required to maintain constitutive eNOS transcriptional activity and that histone eviction rapidly resets histone marks and is a proximal event in the hypoxic repression of eNOS. Although nucleosome eviction has been reported in models of transcriptional activation, the observation that eviction can also accompany transcriptional repression in hypoxic mammalian cells argues that eviction may be broadly relevant to both positive and negative changes in transcription.

Received for publication September 22, 2009. Revision received October 26, 2009.

FOOTNOTES Back to Top

1 Recipient of an Natural Sciences and Engineering Research Council Canada Graduate Scholarship.

2 The recipient of a CIHR Frederick Banting and Charles Best Canada Graduate Scholarship.

3 Recipient of a Career Investigator Award from the Heart and Stroke Foundation of Canada. To whom correspondence should be addressed: Rm. 7358, Medical Sciences Bldg., University of Toronto, 1 King's College Circle, Toronto, Ontario M5S 1A8, Canada. Tel.: 416-978-2441; Fax: 416-978-8765; E-mail: p.marsden{at}utoronto.ca.

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