title: Nitric oxide modifies global histone methylation by inhibiting Jumonji C domain-containing demethylases.
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.affiliation: Department of Medicinal Chemistry, University of Illinois at Chicago, Chicago, Illinois 60612, USA.
authors.forename: Jason R
authors.initials: JR
authors.lastname: Hickok
authors.forename: Divya
authors.initials: D
authors.lastname: Vasudevan
authors.forename: William E
authors.initials: WE
authors.lastname: Antholine
authors.forename: Douglas D
authors.initials: DD
authors.lastname: Thomas
mesh_terms: D000818:Animals; D003067:Coenzymes / Q000378:metabolism*; D015536:Down-Regulation / Q000502:physiology; D044127:Epigenesis, Genetic / Q000502:physiology; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology*; D006649:Histocompatibility Antigens / Q000235:genetics / Q000378:metabolism; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics / Q000378:metabolism; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007501:Iron / Q000378:metabolism*; D056484:Jumonji Domain-Containing Histone Demethylases / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D019169:Jurkat Cells; D008745:Methylation; D051379:Mice; D009569:Nitric Oxide / Q000235:genetics / Q000378:metabolism*
chemical_list: D003067:Coenzymes; D006649:Histocompatibility Antigens; D006657:Histones; D009569:Nitric Oxide; D007501:Iron; D056484:Jumonji Domain-Containing Histone Demethylases; C530247:KDM3A protein, human; C511045:Kdm3a protein, mouse; C445405:EHMT2 protein, human; C533711:G9a protein, mouse; D011495:Histone-Lysine N-Methyltransferase
keywords: Cell Biology; Demethylases; Epigenetics; Histones; Iron; Methyltransferases; Nitric Oxide
references.citation: J Biol Chem. 2009 Jun 26;284(26):17775-82
references.pmid: 19407342
references.citation: Clin Chim Acta. 2010 Oct 9;411(19-20):1401-11
references.pmid: 20598676
references.citation: Proc Natl Acad Sci U S A. 2012 Nov 6;109(45):18499-504
references.pmid: 23093672
references.citation: Cell Rep. 2012 Nov 29;2(5):1233-43
references.pmid: 23168260
references.citation: J Biol Chem. 2010 Mar 26;285(13):9636-9641
references.pmid: 20118233
references.citation: Cell Rep. 2012 Nov 29;2(5):1244-58
references.pmid: 23103168
references.citation: Cell. 2007 Feb 23;128(4):693-705
references.pmid: 17320507
references.citation: Cell Res. 2010 Jul;20(7):794-801
references.pmid: 20531378
references.citation: Proc Natl Acad Sci U S A. 2011 Dec 13;108(50):20178-83
references.pmid: 22123949
references.citation: Cancer Res. 2006 Mar 1;66(5):2600-7
references.pmid: 16510578
references.citation: Nature. 2006 Feb 16;439(7078):811-6
references.pmid: 16362057
references.citation: Genes Dev. 2002 Jul 15;16(14):1779-91
references.pmid: 12130538
references.citation: J Biol Chem. 2012 Dec 28;287(53):44508-17
references.pmid: 23152497
references.citation: Biochem J. 2003 Dec 1;376(Pt 2):537-44
references.pmid: 14531732
references.citation: PLoS One. 2010 Jan 11;5(1):e8570
references.pmid: 20084102
references.citation: Cell. 2006 May 5;125(3):467-81
references.pmid: 16603238
references.citation: Biometals. 2009 Feb;22(1):191-6
references.pmid: 19096759
references.citation: Cell. 2006 May 5;125(3):483-95
references.pmid: 16603237
references.citation: Cancer Res. 2013 May 15;73(10):3019-28
references.pmid: 23492365
references.citation: Cell. 2004 Dec 29;119(7):941-53
references.pmid: 15620353
references.citation: Bioorg Med Chem. 2011 Jun 15;19(12):3625-36
references.pmid: 21596573
references.citation: J Chromatogr B Analyt Technol Biomed Life Sci. 2007 May 15;851(1-2):93-105
references.pmid: 17208057
references.citation: Curr Pharm Des. 2010;16(4):381-91
references.pmid: 20236067
references.citation: Nat Rev Genet. 2006 Sep;7(9):715-27
references.pmid: 16983801
references.citation: J Cell Biochem. 2011 Feb;112(2):415-24
references.pmid: 21268062
references.citation: Genes Dev. 2006 Jun 15;20(12):1557-62
references.pmid: 16738407
references.citation: Biochemistry. 1994 Mar 29;33(12):3679-87
references.pmid: 8142366
references.citation: Biochemistry. 2007 Jul 24;46(29):8569-78
references.pmid: 17602574
references.citation: Bioessays. 1998 Aug;20(8):615-26
references.pmid: 9780836
references.citation: Free Radic Biol Med. 2008 Jul 1;45(1):18-31
references.pmid: 18439435
references.citation: J Biol Chem. 2008 Dec 26;283(52):36542-52
references.pmid: 18984585
references.citation: Cancer Res. 2010 May 15;70(10):4214-21
references.pmid: 20406991
references.citation: Biochemistry. 2012 Nov 6;51(44):8699-701
references.pmid: 23067339
references.citation: Carcinogenesis. 2009 Jul;30(7):1243-51
references.pmid: 19376846
references.citation: Mol Cell. 2003 Aug;12(2):475-87
references.pmid: 14536086
references.citation: Free Radic Biol Med. 2012 Sep 1;53(5):1041-7
references.pmid: 22841757
references.citation: Nature. 2006 Jul 20;442(7100):307-11
references.pmid: 16732293
references.citation: Sci Transl Med. 2012 May 9;4(133):133ra58
references.pmid: 22472521
references.citation: J Clin Invest. 2012 Apr;122(4):1469-86
references.pmid: 22406531
references.citation: Curr Opin Struct Biol. 2010 Dec;20(6):659-72
references.pmid: 20888218
references.citation: Cytokine. 2011 Feb;53(2):256-62
references.pmid: 21131212
references.citation: Nat Rev Mol Cell Biol. 2012 Apr 04;13(5):297-311
references.pmid: 22473470
references.citation: Int J Oncol. 2013 Apr;42(4):1212-8
references.pmid: 23354547
references.citation: J Biol Chem. 1997 Aug 15;272(33):20340-7
references.pmid: 9252338
references.citation: J Biol Chem. 2011 Dec 2;286(48):41413-41424
references.pmid: 21976667
references.citation: Cell Stem Cell. 2012 Jul 6;11(1):50-61
references.pmid: 22770241
references.citation: Cell Res. 2010 Feb;20(2):154-65
references.pmid: 20084082
references.citation: J Biol Chem. 2008 Oct 24;283(43):28926-33
references.pmid: 18480062
references.citation: Curr Med Chem. 2005;12(23):2711-29
references.pmid: 16305467
references.citation: Trends Biochem Sci. 2011 Jan;36(1):7-18
references.pmid: 20728359
references.citation: J Biol Chem. 2010 Jun 25;285(26):20234-41
references.pmid: 20404330
references.citation: J Clin Invest. 2013 Feb;123(2):727-39
references.pmid: 23321669
references.citation: Mol Cell Biol. 2006 May;26(10):3728-37
references.pmid: 16648469
references.citation: Cardiovasc Res. 2006 Sep 1;71(4):642-51
references.pmid: 16780822
references.citation: Biochem J. 2013 Jan 15;449(2):491-6
references.pmid: 23092293
references.citation: Cancer Res. 2006 Sep 15;66(18):9009-16
references.pmid: 16982742
references.citation: Nature. 2006 Jul 20;442(7100):312-6
references.pmid: 16732292
references.citation: Science. 2001 Apr 20;292(5516):468-72
references.pmid: 11292861
references.citation: Int J Cancer. 2010 Nov 1;127(9):1991-8
references.pmid: 20607829
references.citation: Antioxid Redox Signal. 2011 Jul 15;15(2):551-89
references.pmid: 20919933
references.citation: Proc Natl Acad Sci U S A. 2004 Jun 15;101(24):8894-9
references.pmid: 15178764
references.citation: PLoS One. 2012;7(12):e51407
references.pmid: 23236496
references.citation: J Biol Chem. 2010 Mar 5;285(10):7374-83
references.pmid: 20042601
references.citation: Free Radic Biol Med. 2011 Oct 15;51(8):1558-66
references.pmid: 21787861
references.citation: Genes Dev. 2005 Apr 1;19(7):815-26
references.pmid: 15774718
references.citation: Neoplasma. 2011;58(2):153-7
references.pmid: 21275466
references.citation: Biochem J. 2008 Dec 15;416(3):387-94
references.pmid: 18713068
references.citation: Nat Rev Genet. 2009 Apr;10(4):241-51
references.pmid: 19293820
references.citation: Blood. 2013 Mar 28;121(13):2462-73
references.pmid: 23365460
references.citation: Int J Cancer. 2012 Aug 1;131(3):E179-89
references.pmid: 22020899
references.citation: Cell Signal. 2010 Mar;22(3):349-56
references.pmid: 19861159
references.citation: Antioxid Redox Signal. 2012 Oct 1;17(7):962-8
references.pmid: 22304688
references.citation: Nat Rev Mol Cell Biol. 2005 Nov;6(11):838-49
references.pmid: 16261189
references.citation: Mol Biol Cell. 2003 Aug;14(8):3470-81
references.pmid: 12925778
references.citation: J Mol Biol. 2011 Jul 8;410(2):268-79
references.pmid: 21601578
references.citation: J Physiol Pharmacol. 2002 Dec;53(4 Pt 1):503-14
references.pmid: 12512688
references.citation: Biochem Biophys Res Commun. 2008 Aug 8;372(4):892-7
references.pmid: 18538129
references.citation: Mol Cell. 2003 Dec;12(6):1577-89
references.pmid: 14690609
references.citation: Carcinogenesis. 2010 Dec;31(12):2136-44
references.pmid: 20881000