title: Disruption of histone modification and CARM1 recruitment by arsenic represses transcription at glucocorticoid receptor-regulated promoters.
abstract: Chronic exposure to inorganic arsenic (iAs) found in the environment is one of the most significant and widespread environmental health risks in the U.S. and throughout the world. It is associated with a broad range of health effects from cancer to diabetes as well as reproductive and developmental anomalies. This diversity of diseases can also result from disruption of metabolic and other cellular processes regulated by steroid hormone receptors via aberrant transcriptional regulation. Significantly, exposure to iAs inhibits steroid hormone-mediated gene activation. iAs exposure is associated with disease, but is also used therapeutically to treat specific cancers complicating an understanding of iAs action. Transcriptional activation by steroid hormone receptors is accompanied by changes in histone and non-histone protein post-translational modification (PTM) that result from the enzymatic activity of coactivator and corepressor proteins such as GRIP1 and CARM1. This study addresses how iAs represses steroid receptor-regulated gene transcription. PTMs on histones H3 and H4 at the glucocorticoid receptor (GR)-activated mouse mammary tumor virus (MMTV) promoter were identified by chromatin immunoprecipitation analysis following exposure to steroid hormone+/-iAs. Histone H3K18 and H3R17 amino acid residues had significantly different patterns of PTMs after treatment with iAs. Promoter interaction of the coactivator CARM1 was disrupted, but the interaction of GRIP1, a p160 coactivator through which CARM1 interacts with a promoter, was intact. Over-expression of CARM1 was able to fully restore and GRIP1 partially restored iAs-repressed transcription indicating that these coactivators are functionally associated with iAs-mediated transcriptional repression. Both are essential for robust transcription at steroid hormone regulated genes and both are associated with disease when inappropriately expressed. We postulate that iAs effects on CARM1 and GRIP1 may underlie some of its therapeutic effects and as well be associated with its toxic effects.
authors.affiliation: Department of Physiology, Dartmouth Medical School, Lebanon, New Hampshire, USA.
authors.forename: Fiona D
authors.initials: FD
authors.lastname: Barr
authors.forename: Lori J
authors.initials: LJ
authors.lastname: Krohmer
authors.forename: Joshua W
authors.initials: JW
authors.lastname: Hamilton
authors.forename: Lynn A
authors.initials: LA
authors.lastname: Sheldon
mesh_terms: D000818:Animals; D001151:Arsenic / Q000494:pharmacology*; D045744:Cell Line, Tumor; D015500:Chloramphenicol O-Acetyltransferase / Q000235:genetics; D047369:Chromatin Immunoprecipitation; D024202:Electrophoretic Mobility Shift Assay; D006657:Histones / Q000378:metabolism*; D051379:Mice; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic; D011484:Protein-Arginine N-Methyltransferases / Q000378:metabolism*; D011965:Receptors, Glucocorticoid / Q000502:physiology*; D014158:Transcription, Genetic / Q000187:drug effects*
chemical_list: D006657:Histones; D011965:Receptors, Glucocorticoid; D011484:Protein-Arginine N-Methyltransferases; C119966:coactivator-associated arginine methyltransferase 1; D015500:Chloramphenicol O-Acetyltransferase; D001151:Arsenic
references.citation: Science. 2002 Jun 21;296(5576):2145-6
references.pmid: 12077388
references.citation: Chem Res Toxicol. 2004 Aug;17(8):1064-76
references.pmid: 15310238
references.citation: Cell. 2004 Jun 11;117(6):735-48
references.pmid: 15186775
references.citation: Nature. 2000 Jan 6;403(6765):41-5
references.pmid: 10638745
references.citation: Proc Natl Acad Sci U S A. 1996 May 14;93(10):4948-52
references.pmid: 8643509
references.citation: EMBO J. 1987 Nov;6(11):3333-40
references.pmid: 3123217
references.citation: Annu Rev Biochem. 1994;63:451-86
references.pmid: 7979245
references.citation: Mol Cell Biol. 2003 Jun;23(11):3763-73
references.pmid: 12748280
references.citation: Cell. 2007 Feb 23;128(4):693-705
references.pmid: 17320507
references.citation: Mol Cell. 2007 Sep 7;27(5):691-700
references.pmid: 17803935
references.citation: Mol Cell Biol. 1989 Jul;9(7):3127-31
references.pmid: 2550796
references.citation: Mol Cell Biol. 2001 Nov;21(21):7172-82
references.pmid: 11585900
references.citation: Mol Cell Biol. 2007 Oct;27(20):7089-101
references.pmid: 17682057
references.citation: Science. 1999 Jun 25;284(5423):2174-7
references.pmid: 10381882
references.citation: Environ Health Perspect. 2001 Mar;109(3):245-51
references.pmid: 11333185
references.citation: Mol Cell Endocrinol. 2008 Jan 2;280(1-2):1-5
references.pmid: 17935877
references.citation: J Biol Chem. 2006 Aug 11;281(32):22446-52
references.pmid: 16762916
references.citation: Nucl Recept Signal. 2008 Feb 01;6:e001
references.pmid: 18301781
references.citation: Mol Cell Biol. 2009 Apr;29(7):1909-21
references.pmid: 19188441
references.citation: Mol Endocrinol. 2009 Mar;23(3):412-21
references.pmid: 19131511
references.citation: Mol Endocrinol. 2001 Apr;15(4):485-500
references.pmid: 11266502
references.citation: EMBO J. 1987 Aug;6(8):2321-8
references.pmid: 2822386
references.citation: Mol Biol Cell. 2008 Aug;19(8):3308-22
references.pmid: 18508913
references.citation: Carcinogenesis. 2008 Sep;29(9):1831-6
references.pmid: 18321869
references.citation: Proc Natl Acad Sci U S A. 2007 Jul 24;104(30):12318-23
references.pmid: 17640894
references.citation: Biochemistry. 2001 May 15;40(19):5747-56
references.pmid: 11341840
references.citation: Mol Endocrinol. 2006 May;20(5):971-83
references.pmid: 16410316
references.citation: Nat Med. 2008 Dec;14(12):1333-42
references.pmid: 19029980
references.citation: Cell Signal. 2007 Jun;19(6):1101-12
references.pmid: 17368849
references.citation: Physiol Rev. 2007 Jul;87(3):905-31
references.pmid: 17615392
references.citation: Mol Cell Biol. 2000 Sep;20(17):6466-75
references.pmid: 10938123
references.citation: Science. 1988 May 13;240(4854):889-95
references.pmid: 3283939
references.citation: Neuron. 2002 Apr 11;34(2):235-44
references.pmid: 11970865
references.citation: Mol Cell Endocrinol. 2007 Sep 15;275(1-2):43-61
references.pmid: 17624658
references.citation: Biochemistry. 1984 Aug 28;23(18):4237-42
references.pmid: 6386046
references.citation: Cell. 1999 Sep 3;98(5):675-86
references.pmid: 10490106
references.citation: Environ Health Perspect. 2008 Feb;116(2):165-72
references.pmid: 18288313
references.citation: J Biol Chem. 2002 Nov 22;277(47):44988-95
references.pmid: 12239215
references.citation: J Biol Chem. 2002 Nov 29;277(48):46066-72
references.pmid: 12351636
references.citation: Genes Dev. 2004 Jan 15;18(2):144-56
references.pmid: 14729568
references.citation: Mol Endocrinol. 2003 Jun;17(6):1085-94
references.pmid: 12637584
references.citation: Genes Dev. 2006 Jun 1;20(11):1405-28
references.pmid: 16751179
references.citation: Mol Cell Biol. 2008 Nov;28(21):6580-93
references.pmid: 18765637
references.citation: Mol Cell Biochem. 2005 Nov;279(1-2):133-9
references.pmid: 16283522
references.citation: Mol Cell Biol. 1998 Jun;18(6):3633-44
references.pmid: 9584204
references.citation: J Biol Chem. 2001 Aug 31;276(35):32423-6
references.pmid: 11448945
references.citation: J Biol Chem. 2003 Apr 11;278(15):13183-91
references.pmid: 12547826
references.citation: Nature. 1994 Jul 21;370(6486):223-6
references.pmid: 7913207
references.citation: Prog Nucleic Acid Res Mol Biol. 2005;79:237-97
references.pmid: 16096030
references.citation: Cell. 2003 Dec 12;115(6):751-63
references.pmid: 14675539
references.citation: Mol Cell Biol. 2006 Nov;26(21):7846-57
references.pmid: 16923966
references.citation: Mol Cell. 2000 Jun;5(6):939-48
references.pmid: 10911988
references.citation: Cell. 2007 Jun 15;129(6):1125-40
references.pmid: 17574025
references.citation: J Biol Chem. 2000 Dec 29;275(52):40810-6
references.pmid: 11010967
references.citation: Mol Cell Biol. 2007 Jan;27(1):120-34
references.pmid: 17043108
references.citation: Mol Cell Biol. 2002 May;22(10):3255-63
references.pmid: 11971959
references.citation: Nucleic Acids Res. 2001 May 1;29(9):e45
references.pmid: 11328886
references.citation: Mol Cell Biol. 2006 May;26(10):3728-37
references.pmid: 16648469
references.citation: Gene Anal Tech. 1988 Mar-Apr;5(2):22-31
references.pmid: 3192155
references.citation: Science. 1997 Aug 15;277(5328):965-8
references.pmid: 9252329
references.citation: J Biol Chem. 1990 Feb 5;265(4):1938-45
references.pmid: 2298732
references.citation: Mol Endocrinol. 2006 Jun;20(6):1276-86
references.pmid: 16322096
references.citation: Mol Cell Biol. 2000 Oct;20(20):7541-9
references.pmid: 11003650
references.citation: Toxicol Sci. 2007 Jul;98(1):75-86
references.pmid: 17283378
references.citation: Mol Endocrinol. 2005 Mar;19(3):574-87
references.pmid: 15563544
references.citation: Genes Dev. 2003 Jul 1;17(13):1617-29
references.pmid: 12842912
references.citation: Curr Biol. 2002 Dec 23;12(24):2090-7
references.pmid: 12498683
references.citation: Mol Cell. 2008 Feb 29;29(4):465-76
references.pmid: 18313384
references.citation: Curr Biol. 2001 Dec 11;11(24):1981-5
references.pmid: 11747826
references.citation: Mol Cell Biol. 2007 Feb;27(4):1296-308
references.pmid: 17158932
references.citation: J Biol Chem. 2001 Apr 27;276(17):13505-8
references.pmid: 11279224
references.citation: Nature. 1998 May 7;393(6680):88-91
references.pmid: 9590696
references.citation: Mol Endocrinol. 2007 Apr;21(4):843-56
references.pmid: 17227884