BRCA1 affects global DNA methylation through regulation of DNMT1.
Global DNA hypomethylation at CpG islands coupled with local hypermethylation is a hallmark for breast cancer, yet the mechanism underlying this change remains elusive. In this study, we showed that DNMT1, which encodes a methylation maintenance enzyme, is a transcriptional target of BRCA1. BRCA1 binds to the promoter of the DNMT1 gene through a potential OCT1 site and the binding is required for maintaining a transcriptional active configuration of the promoter in both mouse and human cells. We further demonstrated that impaired function of BRCA1 leads to global DNA hypomethylation, loss of genomic imprinting, and an open chromatin configuration in several types of tissues examined in a BRCA1 mutant mouse model at premaligant stages. BRCA1 deficiency is also associated with significantly increased expression levels of several protooncogenes, including c-Fos, Ha-Ras, and c-Myc, with a higher expression in tumors, while premalignant mammary epithelial cells displayed an intermediate state between tumors and controls. In human clinical samples, reduced expression of BRCA1 correlates with decreased levels of DNMT1, and reduced methylation of CpG islands. Thus, BRCA1 prevents global DNA hypomethylation through positively regulating DNMT1 expression, and this provides one of mechanisms for BRCA1-associated breast cancer formation.
Shukla
Vivek
V
Genetics of Development and Disease Branch, 10/9N105, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Coumoul
Xavier
X
Lahusen
Tyler
T
Wang
Rui-Hong
RH
Xu
Xiaoling
X
Vassilopoulos
Athanassios
A
Xiao
Cuiying
C
Lee
Mi-Hye
MH
Man
Yan-Gao
YG
Ouchi
Mutsuko
M
Ouchi
Toru
T
Deng
Chu-Xia
CX
D000818:Animals; D019313:BRCA1 Protein / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D001943:Breast Neoplasms / Q000201:enzymology / Q000378:metabolism; D045744:Cell Line, Tumor; D018899:CpG Islands; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics / Q000378:metabolism*; D019175:DNA Methylation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D018392:Genomic Imprinting; D006657:Histones / Q000378:metabolism; D006801:Humans; D008321:Mammary Glands, Animal / Q000166:cytology / Q000378:metabolism; D051379:Mice; D050811:Octamer Transcription Factor-1 / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation
D019313:BRCA1 Protein; D006657:Histones; D050811:Octamer Transcription Factor-1; D016760:Proto-Oncogene Proteins c-fos; D016271:Proto-Oncogene Proteins c-myc; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; C000619380:DNMT1 protein, human; C000619381:Dnmt1 protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)
Oncogene. 2000 Dec 11;19(53):6159-75
11156530
Oncogene. 2007 Nov 8;26(51):7204-12
17496925
Environ Mol Mutagen. 2002;39(2-3):171-7
11921186
Oncogene. 2003 Jan 30;22(4):528-37
12555066
Folia Histochem Cytobiol. 2006;44(3):143-54
16977793
J Biol Chem. 2001 Nov 2;276(44):41399-406
11526114
Adv Exp Med Biol. 2003;532:39-49
12908548
Curr Biol. 2004 Dec 14;14(23):2135-42
15589157
N Engl J Med. 2003 Nov 20;349(21):2042-54
14627790
Proc Natl Acad Sci U S A. 2005 Sep 20;102(38):13580-5
16174748
Cell. 1996 Jun 28;85(7):1009-23
8674108
Curr Top Microbiol Immunol. 2006;301:203-25
16570849
Proc Natl Acad Sci U S A. 2004 Dec 7;101(49):17108-13
15563594
Mech Ageing Dev. 2003 Dec;124(10-12):989-98
14659588
Oncogene. 1998 Dec 17;17(24):3115-24
9872327
Nat Rev Genet. 2009 May;10(5):295-304
19308066
Nat Rev Genet. 2002 Sep;3(9):662-73
12209141
Nat Genet. 2001 Jul;28(3):266-71
11431698
Int J Biol Sci. 2009;5(1):20-7
19119312
Crit Rev Eukaryot Gene Expr. 2000;10(2):179-212
11186332
Cell. 1992 Jun 12;69(6):915-26
1606615
Annu Rev Genomics Hum Genet. 2008;9:197-216
18767963
Int J Biol Sci. 2008;4(6):352-61
18953404
Cell. 2008 Nov 14;135(4):604-7
19013272
Mod Pathol. 2007 Jul;20(7):711-21
17464311
Cell. 2002 Jan 25;108(2):171-82
11832208
Eur J Biochem. 2002 Jun;269(12):2961-70
12071960
Mutat Res. 2008 Mar-Apr;658(3):191-214
18403253
Nat Genet. 2007 Mar;39(3):391-6
17322882
Cancer. 1999 Jan 1;85(1):112-8
9921982
Oncogene. 2001 May 28;20(24):3156-65
11420732
Genes Dev. 2003 Jan 15;17(2):201-13
12533509
Cancer Res. 2006 Jul 15;66(14):7151-7
16849561
Science. 2003 Apr 18;300(5618):489-92
12702876
Cell. 1999 May 28;97(5):575-86
10367887
J Biochem. 2006 Dec;140(6):763-76
17046852
Nat Genet. 1996 Feb;12(2):191-4
8563759
Carcinogenesis. 2007 Jul;28(7):1401-7
17363841
Bioessays. 2000 Aug;22(8):728-37
10918303
Nat Cell Biol. 2006 Apr;8(4):416-24
16565708
Proc Natl Acad Sci U S A. 1999 Oct 12;96(21):11895-9
10518547
Nat Rev Genet. 2001 Apr;2(4):292-301
11283701
Proc Natl Acad Sci U S A. 1995 Jul 18;92(15):6991-5
7624356
Ann Oncol. 2008 Nov;19(11):1870-4
18647968
Mol Cell. 2008 Oct 10;32(1):11-20
18851829
Cancer Epidemiol Biomarkers Prev. 2009 Mar;18(3):901-14
19258476
EMBO J. 2006 May 17;25(10):2167-77
16675955
J Biol Chem. 2010 Jun 18;285(25):19092-105
20185827
Toxicol Sci. 2003 Oct;75(2):289-99
12883089
Science. 1994 Oct 7;266(5182):66-71
7545954
Cancer Biol Ther. 2004 Dec;3(12):1225-31
15539937
J Biol Chem. 2004 Jul 9;279(28):29606-14
15123655
Nucleic Acids Res. 2006 Mar 06;34(5):1416-26
16522651
Development. 1996 Oct;122(10):3195-205
8898232
Development. 2003 May;130(9):2001-12
12642502
Mol Cell Biol. 2003 Aug;23(16):5594-605
12897133
Carcinogenesis. 2000 Mar;21(3):461-7
10688866
Science. 1992 Jan 31;255(5044):603-6
1736363
Acta Biochim Pol. 2006;53(2):245-56
16582985
Int J Biol Sci. 2008 May 04;4(3):133-42
18461147
Nature. 1997 Sep 11;389(6647):187-90
9296497
Hum Mol Genet. 2003 Apr 1;12 Spec No 1:R113-23
12668603