title: Coordinate H3K9 and DNA methylation silencing of ZNFs in toxicant-induced malignant transformation.
abstract: Genome-wide disruption of the epigenetic code is a hallmark of malignancy that encompasses many distinct, highly interactive modifications. Delineating the aberrant epigenome produced during toxicant-mediated malignant transformation will help identify the underlying epigenetic drivers of environmental toxicant-induced carcinogenesis. Gene promoter DNA methylation and gene expression profiling of arsenite-transformed prostate epithelial cells showed a negative correlation between gene expression changes and DNA methylation changes; however, less than 10% of the genes with increased promoter methylation were downregulated. Studies described herein confirm that a majority of the DNA hypermethylation events occur at H3K27me3 marked genes that were already transcriptionally repressed. In contrast to aberrant DNA methylation targeting H3K27me3 pre-marked silent genes, we found that actively expressed C2H2 zinc finger genes (ZNFs) marked with H3K9me3 on their 3' ends, were the favored targets of DNA methylation linked gene silencing. DNA methylation coupled, H3K9me3 mediated gene silencing of ZNF genes was widespread, occurring at individual ZNF genes on multiple chromosomes and across ZNF gene family clusters. At ZNF gene promoters, H3K9me3 and DNA hypermethylation replaced H3K4me3, resulting in a widespread downregulation of ZNF gene expression, which accounted for 8% of all the downregulated genes in the arsenical-transformed cells. In summary, these studies associate toxicant exposure with widespread silencing of ZNF genes by DNA hypermethylation-linked H3K9me3 spreading, further implicating epigenetic dysfunction as a driver of toxicant associated carcinogenesis.
authors: Department of Pharmacology and Toxicology; College of Pharmacy; University of Arizona; Tucson, AZ USA.
authors: Paul L
authors: PL
authors: Severson
authors: National Toxicology Program Laboratory; National Institute of Environmental Health Sciences; Research Triangle Park, NC USA.
authors: Erik J
authors: EJ
authors: Tokar
authors: University of Arizona Cancer Center; Tucson, AZ USA.
authors: Lukas
authors: L
authors: Vrba
authors: National Toxicology Program Laboratory; National Institute of Environmental Health Sciences; Research Triangle Park, NC USA.
authors: Michael P
authors: MP
authors: Waalkes
authors: Department of Pharmacology and Toxicology; College of Pharmacy; University of Arizona; Tucson, AZ USA; University of Arizona Cancer Center; Tucson, AZ USA.
authors: Bernard W
authors: BW
authors: Futscher
mesh_terms: D018053:Arsenites / Q000633:toxicity; D002352:Carrier Proteins / Q000235:genetics*; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D019175:DNA Methylation; D063990:Gene Ontology; D020868:Gene Silencing; D006657:Histones / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008239:Lysine / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics*; D012097:Repressor Proteins; D016335:Zinc Fingers
chemical_list: D018053:Arsenites; C486563:BCL11A protein, human; D002352:Carrier Proteins; D006657:Histones; D009687:Nuclear Proteins; D012097:Repressor Proteins; D008239:Lysine; C015001:arsenite
keywords: C2H2 zinc finger genes; DNA methylation; H3K27me3; H3K4me3; H3K9me3; arsenic; epigenetics; malignant transformation
references: Biochem Biophys Res Commun. 2006 Aug 4;346(3):621-8
references: 16793018
references: Mol Cell. 2009 May 15;34(3):271-84
references: 19450526
references: Cancer Sci. 2006 Jan;97(1):64-71
references: 16367923
references: Epigenetics. 2012 Nov;7(11):1249-57
references: 22983262
references: Carcinogenesis. 2008 Aug;29(8):1500-8
references: 18448484
references: Am J Pathol. 2006 Nov;169(5):1643-51
references: 17071588
references: Biochem Biophys Res Commun. 2004 Dec 24;325(4):1383-92
references: 15555580
references: Endocr Relat Cancer. 2011 Jul 04;18(4):465-78
references: 21636702
references: Biochem Biophys Res Commun. 2005 Jul 22;333(1):206-15
references: 15950191
references: Biochem J. 2012 Jan 15;441(2):645-52
references: 21985173
references: Biochem Biophys Res Commun. 2004 Jul 16;320(1):45-53
references: 15207700
references: Virology. 2011 Mar 15;411(2):273-87
references: 21251689
references: Development. 2013 Feb 1;140(3):519-29
references: 23293284
references: Epigenetics. 2012 Nov;7(11):1238-48
references: 22976526
references: Genome Res. 2011 Nov;21(11):1800-12
references: 21784874
references: Toxicol Sci. 2010 Jul;116(1):44-57
references: 20375083
references: Nature. 2007 Aug 9;448(7154):714-7
references: 17687327
references: Nat Genet. 2005 Aug;37(8):853-62
references: 16007088
references: Anticancer Res. 2001 Jul-Aug;21(4B):3021-9
references: 11712805
references: Oncogene. 2011 Mar 24;30(12):1390-401
references: 21132003
references: Cancer Biol Ther. 2008 Jul;7(7):1146-56
references: 18535405
references: Genome Res. 2011 Dec;21(12):2026-37
references: 21873453
references: Nat Struct Mol Biol. 2008 Nov;15(11):1176-1183
references: 18953337
references: Curr Biol. 2003 Jul 15;13(14):1192-200
references: 12867029
references: Cancer. 2009 Aug 1;115(15):3412-26
references: 19472401
references: Nucleic Acids Res. 2003 Feb 15;31(4):e15
references: 12582260
references: Cell Rep. 2012 Oct 25;2(4):766-73
references: 23041315
references: Bioinformatics. 2007 Jan 15;23(2):257-8
references: 17098774
references: Am J Pathol. 2011 May;178(5):1965-74
references: 21514414
references: Biochem J. 2013 Feb 1;449(3):623-30
references: 23116180
references: PLoS One. 2011 Feb 15;6(2):e17121
references: 21347206
references: Nature. 2006 Feb 16;439(7078):871-4
references: 16357870
references: Nat Genet. 2007 Feb;39(2):232-6
references: 17200670
references: Cancer Res. 1999 Apr 15;59(8):1877-83
references: 10213495
references: Free Radic Biol Med. 2013 Aug;61:249-56
references: 23602911
references: Biochem Biophys Res Commun. 2006 Aug 18;347(1):288-96
references: 16815308
references: PLoS Genet. 2007 Jun;3(6):e89
references: 17542650
references: Cancer Res. 2010 Aug 15;70(16):6516-26
references: 20682794
references: Semin Cancer Biol. 2010 Aug;20(4):246-53
references: 20685251
references: Nucleic Acids Res. 2012 Oct;40(18):8993-9007
references: 22844087
references: Carcinogenesis. 1997 Jun;18(6):1215-23
references: 9214605
references: Genome Res. 2006 Dec;16(12):1493-504
references: 17038565
references: Nat Genet. 2007 Feb;39(2):157-8
references: 17200673
references: Toxicol Appl Pharmacol. 2009 Dec 1;241(2):221-9
references: 19716837
references: Nature. 2010 Jan 14;463(7278):237-40
references: 20075919
references: Biochem Biophys Res Commun. 2005 Aug 12;333(4):1050-9
references: 15964543
references: J Natl Cancer Inst. 2002 Dec 18;94(24):1888-91
references: 12488483
references: PLoS Genet. 2010 Mar 05;6(3):e1000869
references: 20221260
references: Mol Cell Biochem. 2008 Mar;310(1-2):141-51
references: 18084723
references: Int J Cancer. 2002 Apr 10;98(5):713-7
references: 11920640
references: Toxicol Appl Pharmacol. 2005 Aug 15;206(3):288-98
references: 16039940
references: Biochem Biophys Res Commun. 2005 Jul 22;333(1):5-13
references: 15936718