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Nitric oxide modifies global histone methylation by inhibiting Jumonji C domain-containing demethylases.
J Biol Chem. 2013 May 31; 288(22):16004-15.JB

Abstract

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.

Authors+Show Affiliations

Department of Medicinal Chemistry, University of Illinois at Chicago, Chicago, Illinois 60612, USA.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

23546878

Citation

Hickok, Jason R., et al. "Nitric Oxide Modifies Global Histone Methylation By Inhibiting Jumonji C Domain-containing Demethylases." The Journal of Biological Chemistry, vol. 288, no. 22, 2013, pp. 16004-15.
Hickok JR, Vasudevan D, Antholine WE, et al. Nitric oxide modifies global histone methylation by inhibiting Jumonji C domain-containing demethylases. J Biol Chem. 2013;288(22):16004-15.
Hickok, J. R., Vasudevan, D., Antholine, W. E., & Thomas, D. D. (2013). Nitric oxide modifies global histone methylation by inhibiting Jumonji C domain-containing demethylases. The Journal of Biological Chemistry, 288(22), 16004-15. https://doi.org/10.1074/jbc.M112.432294
Hickok JR, et al. Nitric Oxide Modifies Global Histone Methylation By Inhibiting Jumonji C Domain-containing Demethylases. J Biol Chem. 2013 May 31;288(22):16004-15. PubMed PMID: 23546878.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Nitric oxide modifies global histone methylation by inhibiting Jumonji C domain-containing demethylases. AU - Hickok,Jason R, AU - Vasudevan,Divya, AU - Antholine,William E, AU - Thomas,Douglas D, Y1 - 2013/04/01/ PY - 2013/4/3/entrez PY - 2013/4/3/pubmed PY - 2013/8/7/medline KW - Cell Biology KW - Demethylases KW - Epigenetics KW - Histones KW - Iron KW - Methyltransferases KW - Nitric Oxide SP - 16004 EP - 15 JF - The Journal of biological chemistry JO - J Biol Chem VL - 288 IS - 22 N2 - 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. SN - 1083-351X UR - https://www.unboundmedicine.com/medline/citation/23546878/Nitric_oxide_modifies_global_histone_methylation_by_inhibiting_Jumonji_C_domain_containing_demethylases_ L2 - http://www.jbc.org/cgi/pmidlookup?view=long&pmid=23546878 DB - PRIME DP - Unbound Medicine ER -