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♦ 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.