Nitric oxide modifies global histone methylation by inhibiting Jumonji C domain-containing demethylases. J Biol Chem 2013 May 31;288(22):16004-15
Date
04/03/2013Pubmed ID
23546878Pubmed Central ID
PMC3668755DOI
10.1074/jbc.M112.432294Scopus ID
2-s2.0-84878393793 (requires institutional sign-in at Scopus site) 104 CitationsAbstract
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.
Author List
Hickok JR, Vasudevan D, Antholine WE, Thomas DDMESH terms used to index this publication - Major topics in bold
AnimalsCoenzymes
Down-Regulation
Epigenesis, Genetic
Gene Expression Regulation, Enzymologic
Histocompatibility Antigens
Histone-Lysine N-Methyltransferase
Histones
Humans
Iron
Jumonji Domain-Containing Histone Demethylases
Jurkat Cells
Methylation
Mice
Nitric Oxide
