title: Differential DNA methylation regions in cytokine and transcription factor genomic loci associate with childhood physical aggression.
abstract: BACKGROUND
  Animal and human studies suggest that inflammation is associated with behavioral disorders including aggression. We have recently shown that physical aggression of boys during childhood is strongly associated with reduced plasma levels of cytokines IL-1α, IL-4, IL-6, IL-8 and IL-10, later in early adulthood. This study tests the hypothesis that there is an association between differential DNA methylation regions in cytokine genes in T cells and monocytes DNA in adult subjects and a trajectory of physical aggression from childhood to adolescence.
  
  
  RESULTS
  We compared the methylation profiles of the entire genomic loci encompassing the IL-1α, IL-6, IL-4, IL-10 and IL-8 and three of their regulatory transcription factors (TF) NFkB1, NFAT5 and STAT6 genes in adult males on a chronic physical aggression trajectory (CPA) and males with the same background who followed a normal physical aggression trajectory (control group) from childhood to adolescence. We used the method of methylated DNA immunoprecipitation with comprehensive cytokine gene loci and TF loci microarray hybridization, statistical analysis and false discovery rate correction. We found differentially methylated regions to associate with CPA in both the cytokine loci as well as in their transcription factors loci analyzed. Some of these differentially methylated regions were located in known regulatory regions whereas others, to our knowledge, were previously unknown as regulatory areas. However, using the ENCODE database, we were able to identify key regulatory elements in many of these regions that indicate that they might be involved in the regulation of cytokine expression.
  
  
  CONCLUSIONS
  We provide here the first evidence for an association between differential DNA methylation in cytokines and their regulators in T cells and monocytes and male physical aggression.
authors: Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada ; Research Unit on Children's Psycho-Social Maladjustment and Ste-Justine Hospital Research Center, University of Montreal, Montreal, Quebec, Canada ; Sackler Program for Epigenetics and Psychobiology, McGill University, Montreal, Quebec, Canada.
authors: Nadine
authors: N
authors: Provençal
authors: Matthew J
authors: MJ
authors: Suderman
authors: Doretta
authors: D
authors: Caramaschi
authors: Dongsha
authors: D
authors: Wang
authors: Michael
authors: M
authors: Hallett
authors: Frank
authors: F
authors: Vitaro
authors: Richard E
authors: RE
authors: Tremblay
authors: Moshe
authors: M
authors: Szyf
mesh_terms: D000328:Adult; D000374:Aggression; D016022:Case-Control Studies; D002648:Child; D016207:Cytokines / Q000097:blood / Q000235:genetics*; D019175:DNA Methylation / Q000235:genetics*; D056726:Genetic Association Studies; D056426:Genetic Loci / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D015894:Genome, Human / Q000235:genetics*; D006801:Humans; D008297:Male; D050800:STAT6 Transcription Factor / Q000235:genetics; D017422:Sequence Analysis, DNA; D013601:T-Lymphocytes / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics*; D014158:Transcription, Genetic
chemical_list: D016207:Cytokines; D050800:STAT6 Transcription Factor; C494101:STAT6 protein, human; D014157:Transcription Factors
references: Monogr Soc Res Child Dev. 2004;69(4):vii, 1-129
references: 15667346
references: Proc Natl Acad Sci U S A. 2010 May 18;107(20):9470-5
references: 20439746
references: Dev Psychopathol. 2010 Winter;22(1):133-50
references: 20102652
references: Brain Behav Immun. 2006 Nov;20(6):507-14
references: 16938427
references: Leukemia. 2000 Nov;14(11):1915-20
references: 11069027
references: J Immunol. 2002 Jul 15;169(2):647-50
references: 12097365
references: Nat Neurosci. 2009 Mar;12(3):342-8
references: 19234457
references: Brain Behav Immun. 2011 Nov;25(8):1548-53
references: 21600281
references: Epigenetics. 2008 Mar-Apr;3(2):97-106
references: 18536531
references: Clin Exp Med. 2010 Sep;10(3):143-52
references: 19949830
references: Proc Natl Acad Sci U S A. 2008 Nov 4;105(44):17046-9
references: 18955703
references: PLoS One. 2013 Jul 26;8(7):e69481
references: 23922720
references: Eur J Pharmacol. 2012 Aug 5;688(1-3):76-83
references: 22634167
references: Psychol Med. 2011 May;41(5):997-1007
references: 20836906
references: PLoS One. 2012;7(6):e39501
references: 22745770
references: J Clin Endocrinol Metab. 2005 May;90(5):2522-30
references: 15705924
references: Nat Genet. 2006 Feb;38(2):149-53
references: 16444255
references: Dev Psychol. 2000 Jul;36(4):463-72
references: 10902698
references: Immunity. 2006 Apr;24(4):369-79
references: 16618596
references: Lancet. 2002 Oct 5;360(9339):1083-8
references: 12384003
references: J Neurosci. 2012 Oct 31;32(44):15626-42
references: 23115197
references: Genome Res. 2012 Oct;22(10):2043-53
references: 22593555
references: Eur J Oral Sci. 2012 Feb;120(1):14-20
references: 22288916
references: Arch Gen Psychiatry. 2007 Nov;64(11):1305-12
references: 17984399
references: Genes Dev. 2009 Sep 15;23(18):2124-33
references: 19759261
references: Hum Psychopharmacol. 2004 Aug;19(6):397-403
references: 15303243
references: Proc Natl Acad Sci U S A. 2008 Jan 15;105(2):751-6
references: 18178625
references: Brain Behav Immun. 2007 Oct;21(7):901-12
references: 17475444
references: Eur J Neurosci. 1998 Dec;10(12):3664-72
references: 9875345
references: PLoS One. 2011 Feb 28;6(2):e14739
references: 21386994
references: J Child Psychol Psychiatry. 2006 Aug;47(8):791-800
references: 16898993
references: Horm Behav. 2006 Nov;50(4):632-9
references: 16876168
references: Dis Markers. 2011;30(2-3):111-21
references: 21508515
references: Dev Psychopathol. 2005 Winter;17(1):167-84
references: 15971765
references: Annu Rev Immunol. 2006;24:607-56
references: 16551261
references: Ann N Y Acad Sci. 2004 Jun;1024:182-212
references: 15265782
references: Immunity. 2002 May;16(5):649-60
references: 12049717
references: Child Dev. 1999 Sep-Oct;70(5):1181-96
references: 10546339
references: J Child Psychol Psychiatry. 2010 Apr;51(4):341-67
references: 20146751
references: J Cell Sci. 2004 Dec 1;117(Pt 25):5965-73
references: 15564374
references: Dev Psychopathol. 2012 Feb;24(1):143-55
references: 22123582
references: Physiol Genomics. 2006 Mar 13;25(1):16-28
references: 16380407
references: Int J Epidemiol. 2012 Feb;41(1):62-74
references: 22422449
references: Am J Psychiatry. 2011 Nov;168(11):1164-70
references: 21799065
references: Neuropsychobiology. 2008;58(2):71-80
references: 18832862
references: Immunol Rev. 2010 Nov;238(1):63-75
references: 20969585
references: J Abnorm Child Psychol. 2006 Feb;34(1):71-85
references: 16565888
references: J Leukoc Biol. 2010 Jun;87(6):1011-8
references: 20335310
references: Proc Natl Acad Sci U S A. 2007 Dec 4;104(49):19351-6
references: 18042717
references: Biol Psychiatry. 2007 Feb 1;61(3):405-11
references: 16950214
references: Nat Neurosci. 2013 Jan;16(1):33-41
references: 23201972
references: Curr Neuropharmacol. 2007;5(2):135-47
references: 18615178
references: Cancer Epidemiol Biomarkers Prev. 2008 Sep;17(9):2306-10
references: 18768498
references: Front Neuroendocrinol. 2009 Oct;30(4):497-518
references: 19341763
references: J Neuroimmunol. 1998 Dec 1;92(1-2):160-9
references: 9916891
references: Dev Psychol. 2003 Mar;39(2):222-45
references: 12661883
references: Nat Rev Genet. 2007 Apr;8(4):253-62
references: 17363974
references: J Abnorm Psychol. 1995 Nov;104(4):614-24
references: 8530764
references: Antiviral Res. 2010 Mar;85(3):463-9
references: 19857525
references: Genes Immun. 2008 Oct;9(7):582-90
references: 18615092
references: Cytokine. 2008 May;42(2):256-264
references: 18406623
references: Genome Biol. 2004;5(10):R80
references: 15461798
references: Proc Natl Acad Sci U S A. 2004 Nov 9;101(45):16010-5
references: 15507491
references: Am J Med Genet B Neuropsychiatr Genet. 2011 Sep;156B(6):700-8
references: 21714072
references: J Child Psychol Psychiatry. 2006 Jan;47(1):30-6
references: 16405638
references: Psychoneuroendocrinology. 2007 Feb;32(2):133-9
references: 17207585
references: Neuroimmunomodulation. 2010;17(3):192-5
references: 20134200
references: Biol Psychol. 2013 Apr;93(1):132-7
references: 23348558
references: J Child Psychol Psychiatry. 2001 May;42(4):451-61
references: 11383961
references: Trends Neurosci. 2001 Dec;24(12):713-9
references: 11718876
references: Mol Cell Biol. 2003 Aug;23(15):5293-300
references: 12861015
references: Child Dev. 2006 Jul-Aug;77(4):954-66
references: 16942499
references: Biol Psychiatry. 2010 Mar 1;67(5):446-57
references: 20015486
references: Cytogenet Cell Genet. 2001;93(3-4):239-41
references: 11528118
references: EMBO J. 2011 Aug 16;30(20):4198-210
references: 21847099
references: J Psychiatr Res. 2007 Nov;41(9):744-52
references: 16901505
references: Brain Behav Immun. 2007 Jan;21(1):9-19
references: 17070667
references: Curr Opin Immunol. 2000 Dec;12(6):654-9
references: 11102768
references: Depress Anxiety. 2009;26(5):447-55
references: 19319993
references: Arch Gen Psychiatry. 2001 Apr;58(4):389-94
references: 11296100
references: Child Dev. 2013 Jan-Feb;84(1):58-75
references: 21883162
references: Environ Health Perspect. 2006 Apr;114(4):567-72
references: 16581547
references: Jpn Circ J. 2001 Oct;65(10):858-62
references: 11665788
references: J Periodontol. 2010 Sep;81(9):1336-41
references: 20450371
references: Genomics. 2006 Mar;87(3):417-26
references: 16378710
references: Pediatrics. 2004 Jul;114(1):e43-50
references: 15231972
references: Biochim Biophys Acta. 1984 Sep 10;782(4):331-42
references: 6383476
references: Bioinformatics. 2003 Jan 22;19(2):185-93
references: 12538238
references: J Neural Transm (Vienna). 2005 Aug;112(8):1083-96
references: 15583952
references: Arch Gen Psychiatry. 2007 May;64(5):592-9
references: 17485611
references: Physiol Genomics. 2004 Jun 17;18(1):43-50
references: 15084713
references: Arthritis Rheum. 2008 Sep;58(9):2686-93
references: 18759290
references: J Abnorm Child Psychol. 1991 Jun;19(3):285-300
references: 1865046
references: Nucleic Acids Res. 1994 Aug 11;22(15):2990-7
references: 8065911
references: Arch Gen Psychiatry. 2008 Oct;65(10):1185-92
references: 18838635
references: Brain Behav Immun. 2002 Dec;16(6):675-84
references: 12480498
references: J Immunol. 2005 Dec 1;175(11):7437-46
references: 16301651
references: Brain Behav Immun. 2011 Feb;25(2):335-9
references: 20951793
references: Am J Orthopsychiatry. 1989 Jul;59(3):355-67
references: 2764070
references: Epigenetics. 2011 Aug;6(8):971-8
references: 21772123
references: Neuropsychopharmacology. 2010 Dec;35(13):2617-23
references: 20881945