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

作者：Hickok Jason R; Vasudevan Divya; Antholine William E; Thomas Douglas D^*

来源：JOURNAL OF BIOLOGICAL CHEMISTRY, 2013, 288(22): 16004-16015.

DOI：10.1074/jbc.M112.432294

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) alpha-ketoglutarate family of proteins performs the majority of histone demethylation. We demonstrate that nitric oxide ((NO)-N-center dot) 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)-N-center dot 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)-N-center dot, 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)-N-center dot. Taken together, these data reveal three novel and distinct mechanisms whereby (NO)-N-center dot 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)-N-center dot as an epigenetic modulator provides a novel explanation for nonclassical gene regulation by (NO)-N-center dot.

• 出版日期2013-5-31