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Logo of jbcThe Journal of Biological Chemistry
J Biol Chem. 2013 May 31; 288(22): 16016.
PMCID: PMC3668756

Role of Nitric Oxide in Regulating Histone Methylation♦

Nitric Oxide Modifies Global Histone Methylation by Inhibiting Jumonji C Domain-containing Demethylases

♦ See referenced article, J. Biol. Chem. 2013, 288, 16004–16015

The continuous methylation and demethylation of lysine residues on histone tails are integral and dynamic aspects of epigenetic regulation. In this Paper of the Week, a team led by Douglas D. Thomas at the University of Illinois at Chicago showed that nitric oxide, a biological free radical commonly denoted as NO, directly inhibited the activity of the demethylase KDM3A. The predominant substrate for this demethylase is Lys-9 of histone 3. In vitro studies established that NO exerted its inhibitory effect by forming a nitrosyliron complex in the catalytic pocket of the enzyme. The investigators then demonstrated that, in cellular systems, NO altered global histone methylation through three distinct mechanisms. First, NO inhibited KDM3A and increased dimethylation at Lys-9 of histone 3. Second, the expression of the methyl-modifying enzymes that target this residue was differentially regulated by NO. Third, by forming dinitrosyliron complexes, NO depleted the iron source that is required as a cofactor for KDM3A activity. “Our results highlight the importance of non-heme, iron·nitrosyl complexes and provide a direct link between NO and significant epigenetic modifications,” say the authors, adding that their model of NO as an epigenetic modulator “provides a novel explanation for nonclassical gene regulation.” Taken together, these results establish NO as an endogenously produced epigenetic regulatory molecule.

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Mechanisms of NO-mediated epigenetic regulation.

Articles from The Journal of Biological Chemistry are provided here courtesy of American Society for Biochemistry and Molecular Biology