Nitric oxide modifies global histone methylation by inhibiting Jumonji C domain-containing demethylases.
Methylation of lysine residues on histone tails is an important epigenetic modification that is dynamically regulated through the combined effects of methyltransferases and demethylases. The Jumonji C domain Fe(II) α-ketoglutarate family of proteins performs the majority of histone demethylation. We demonstrate that nitric oxide ((•)NO) directly inhibits the activity of the demethylase KDM3A by forming a nitrosyliron complex in the catalytic pocket. Exposing cells to either chemical or cellular sources of (•)NO resulted in a significant increase in dimethyl Lys-9 on histone 3 (H3K9me2), the preferred substrate for KDM3A. G9a, the primary methyltransferase acting on H3K9me2, was down-regulated in response to (•)NO, and changes in methylation state could not be accounted for by methylation in general. Furthermore, cellular iron sequestration via dinitrosyliron complex formation correlated with increased methylation. The mRNA of several histone demethylases and methyltransferases was also differentially regulated in response to (•)NO. Taken together, these data reveal three novel and distinct mechanisms whereby (•)NO can affect histone methylation as follows: direct inhibition of Jumonji C demethylase activity, reduction in iron cofactor availability, and regulation of expression of methyl-modifying enzymes. This model of (•)NO as an epigenetic modulator provides a novel explanation for nonclassical gene regulation by (•)NO.
['Hickok|Jason R|JR|', 'Vasudevan|Divya|D|', 'Antholine|William E|WE|', 'Thomas|Douglas D|DD|']
D000818:Animals D003067:Coenzymes D015536:Down-Regulation D044127:Epigenesis, Genetic D015971:Gene Expression Regulation, Enzymologic D006649:Histocompatibility Antigens D011495:Histone-Lysine N-Methyltransferase D006657:Histones D006801:Humans D007501:Iron D056484:Jumonji Domain-Containing Histone Demethylases D019169:Jurkat Cells D008745:Methylation D051379:Mice D009569:Nitric Oxide
Nitric Oxide Histones Demethylases Epigenetics Methyltransferases Iron Cell Biology