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Histone Eviction During Hypoxia

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Science Signaling  12 Jan 2010:
Vol. 3, Issue 104, pp. ec10
DOI: 10.1126/scisignal.3104ec10

Hypoxia has dramatic effects on the circulation, and endothelial cells respond with a distinct change in gene expression, including a reduction in the abundance of endothelial nitric oxide synthase (eNOS), which contributes to hypoxia-induced vasoconstriction. Histone methylation and acetylation influence gene expression by affecting the accessibility of genes to transcription factors and RNA polymerase. Fish et al. found that hypoxia triggered a rapid decrease in all histone acetylation (histones H3 and H4) and rapid loss of RNA polymerase II from the eNOS promoter and a rapid decrease in eNOS transcription in cultured endothelial cells. The rapid change in histone acetylation appeared to be mediated by removal of histones from specific regions of the promoter in response to hypoxia. Furthermore, the unusual histone H2A.Z was specifically associated with the eNOS promoter in endothelial cells, but not in vascular smooth muscle cells, and the abundance of this histone at the endothelial cell eNOS promoter was also reduced after short-term exposure of the cells to hypoxia. If cells were exposed to hypoxia for longer periods, histones were restored to the promoter; however, acetylation continued to decrease at the promoter, suggesting that the returning histones were not reacetylated providing that hypoxic conditions persisted. However, if the cells were returned to normoxic conditions, eNOS transcription, histone acetylation, and the abundance of RNA polymerase II at the promoter were all restored. Although nucleosome accessibility to the proximal region of the eNOS promoter was unchanged (despite histone eviction from this region) in response to short-term hypoxia, after longer periods of hypoxia nucleosome accessibility was decreased, which is consistent with the hypoacetylation of the reassociated histones. Knockdown of the chromatin remodeling subunit BRG1 prevented the return of eNOS expression after reoxygenation, and the eNOS promoter had reduced amounts of H4 after reoxygenation in BRG1-deficient cells. Thus, chromatin remodeling in the form of histone exchange appears to play key roles in both the reduction in eNOS transcription associated with hypoxia and the restoration of expression after reoxygenation.

J. E. Fish, M. S. Yan, C. C. Matouk, R. St. Bernard, J. J. D. Ho Jr., A. Gavryushova, D. Srivastava, P. A. Marsden, Hypoxic repression of endothelial nitric-oxide synthase transcription is coupled with eviction of promoter histones. J. Biol. Chem. 285, 810–826 (2010). [Abstract] [Full Text]

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