title: BRCA1 affects global DNA methylation through regulation of DNMT1.
abstract: 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.
authors.affiliation: Genetics of Development and Disease Branch, 10/9N105, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Vivek
authors.initials: V
authors.lastname: Shukla
authors.forename: Xavier
authors.initials: X
authors.lastname: Coumoul
authors.forename: Tyler
authors.initials: T
authors.lastname: Lahusen
authors.forename: Rui-Hong
authors.initials: RH
authors.lastname: Wang
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Xu
authors.forename: Athanassios
authors.initials: A
authors.lastname: Vassilopoulos
authors.forename: Cuiying
authors.initials: C
authors.lastname: Xiao
authors.forename: Mi-Hye
authors.initials: MH
authors.lastname: Lee
authors.forename: Yan-Gao
authors.initials: YG
authors.lastname: Man
authors.forename: Mutsuko
authors.initials: M
authors.lastname: Ouchi
authors.forename: Toru
authors.initials: T
authors.lastname: Ouchi
authors.forename: Chu-Xia
authors.initials: CX
authors.lastname: Deng
mesh_terms: 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
chemical_list: 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)
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