title: Oxidative damage targets complexes containing DNA methyltransferases, SIRT1, and polycomb members to promoter CpG Islands.
abstract: Cancer cells simultaneously harbor global losses and gains in DNA methylation. We demonstrate that inducing cellular oxidative stress by hydrogen peroxide treatment recruits DNA methyltransferase 1 (DNMT1) to damaged chromatin. DNMT1 becomes part of a complex(es) containing DNMT3B and members of the polycomb repressive complex 4. Hydrogen peroxide treatment causes relocalization of these proteins from non-GC-rich to GC-rich areas. Key components are similarly enriched at gene promoters in an in vivo colitis model. Although high-expression genes enriched for members of the complex have histone mark and nascent transcription changes, CpG island-containing low-expression genes gain promoter DNA methylation. Thus, oxidative damage induces formation and relocalization of a silencing complex that may explain cancer-specific aberrant DNA methylation and transcriptional silencing.
authors.affiliation: Department of Oncology and The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, The Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
authors.forename: Heather M
authors.initials: HM
authors.lastname: O'Hagan
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.forename: Subhojit
authors.initials: S
authors.lastname: Sen
authors.forename: Christina
authors.initials: C
authors.lastname: Destefano Shields
authors.forename: Stella S
authors.initials: SS
authors.lastname: Lee
authors.forename: Yang W
authors.initials: YW
authors.lastname: Zhang
authors.forename: Eriko G
authors.initials: EG
authors.lastname: Clements
authors.forename: Yi
authors.initials: Y
authors.lastname: Cai
authors.forename: Leander
authors.initials: L
authors.lastname: Van Neste
authors.forename: Hariharan
authors.initials: H
authors.lastname: Easwaran
authors.forename: Robert A
authors.initials: RA
authors.lastname: Casero
authors.forename: Cynthia L
authors.initials: CL
authors.lastname: Sears
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Baylin
mesh_terms: D000818:Animals; D002843:Chromatin / Q000378:metabolism; D003092:Colitis / Q000235:genetics; D018899:CpG Islands; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000378:metabolism / Q000502:physiology*; D019175:DNA Methylation; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D045325:HCT116 Cells; D006657:Histones / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D018384:Oxidative Stress; D063146:Polycomb-Group Proteins; D011401:Promoter Regions, Genetic; D012097:Repressor Proteins / Q000378:metabolism / Q000502:physiology; D056564:Sirtuin 1 / Q000378:metabolism / Q000502:physiology*; D000097584:DNA Methyltransferase 3B
chemical_list: D002843:Chromatin; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; D006657:Histones; D006861:Hydrogen Peroxide; D063146:Polycomb-Group Proteins; D012097:Repressor Proteins; D056564:Sirtuin 1; D000097584:DNA Methyltransferase 3B; C000619380:DNMT1 protein, human; C000619381:Dnmt1 protein, mouse; C447939:SIRT1 protein, human
references.citation: Mol Cell Biol. 2005 Jun;25(12):4903-13
references.pmid: 15923609
references.citation: Nature. 2010 Apr 15;464(7291):1082-6
references.pmid: 20393567
references.citation: Cell. 2008 Nov 28;135(5):907-18
references.pmid: 19041753
references.citation: Nature. 2002 Apr 4;416(6880):552-6
references.pmid: 11932749
references.citation: Proc Natl Acad Sci U S A. 2011 Sep 13;108(37):15354-9
references.pmid: 21876161
references.citation: Nucleic Acids Res. 2007;35(7):2191-8
references.pmid: 17355984
references.citation: Nat Genet. 2007 Feb;39(2):237-42
references.pmid: 17211412
references.citation: J Biol Chem. 2007 Mar 30;282(13):9962-9972
references.pmid: 17259173
references.citation: Mol Cell. 2010 Jul 30;39(2):247-58
references.pmid: 20670893
references.citation: Cell. 1999 May 28;97(5):609-20
references.pmid: 10367890
references.citation: Cancer Res. 2008 Jul 15;68(14):5753-9
references.pmid: 18632628
references.citation: Nat Med. 2009 Sep;15(9):1016-22
references.pmid: 19701202
references.citation: Cancer Res. 2008 Dec 15;68(24):10280-9
references.pmid: 19074896
references.citation: Cancer Res. 2010 Oct 15;70(20):8015-24
references.pmid: 20736368
references.citation: Cancer Res. 2007 Jun 1;67(11):5097-102
references.pmid: 17545586
references.citation: BMC Bioinformatics. 2007 Jun 26;8:221
references.pmid: 17594472
references.citation: Clin Vaccine Immunol. 2006 Jan;13(1):132-8
references.pmid: 16426010
references.citation: Proc Natl Acad Sci U S A. 2005 Feb 8;102(6):1859-64
references.pmid: 15684044
references.citation: PLoS Genet. 2006 Mar;2(3):e40
references.pmid: 16596166
references.citation: Cell. 1999 Oct 29;99(3):247-57
references.pmid: 10555141
references.citation: Mol Cell Biol. 2009 Oct;29(19):5366-76
references.pmid: 19620278
references.citation: Cell. 2007 Feb 23;128(4):683-92
references.pmid: 17320506
references.citation: Nature. 2006 Feb 16;439(7078):871-4
references.pmid: 16357870
references.citation: Nat Genet. 2007 Feb;39(2):232-6
references.pmid: 17200670
references.citation: EMBO J. 2002 Aug 1;21(15):4183-95
references.pmid: 12145218
references.citation: Int J Cancer. 2007 Dec 1;121(11):2381-6
references.pmid: 17893868
references.citation: Cell. 1992 Nov 27;71(5):865-73
references.pmid: 1423634
references.citation: BMC Cancer. 2006 Oct 03;6:235
references.pmid: 17018150
references.citation: Cytogenet Genome Res. 2010;128(1-3):17-27
references.pmid: 20407218
references.citation: Infect Immun. 2009 Apr;77(4):1708-18
references.pmid: 19188353
references.citation: PLoS Genet. 2008 Aug 15;4(8):e1000155
references.pmid: 18704159
references.citation: Nat Genet. 2007 Feb;39(2):157-8
references.pmid: 17200673
references.citation: Biol Chem. 1997 Nov;378(11):1293-7
references.pmid: 9426189
references.citation: J Cell Biol. 2007 Feb 26;176(5):565-71
references.pmid: 17312023
references.citation: Proc Natl Acad Sci U S A. 1997 Aug 19;94(17):9463-8
references.pmid: 9256505
references.citation: J Cell Biol. 1999 Sep 6;146(5):905-16
references.pmid: 10477747
references.citation: Hum Mol Genet. 2011 Jan 1;20(1):126-40
references.pmid: 20940144
references.citation: J Biol Chem. 1998 Mar 6;273(10):5858-68
references.pmid: 9488723
references.citation: Methods. 2003 Dec;31(4):265-73
references.pmid: 14597310