BRCA1 affects global DNA methylation through regulation of DNMT1

• Published in: Cell research Vol. 20; no. 11; pp. 1201 - 1215
• Main Authors: Shukla, Vivek, Coumoul, Xavier, Lahusen, Tyler, Wang, Rui-Hong, Xu, Xiaoling, Vassilopoulos, Athanassios, Xiao, Cuiying, Lee, Mi-Hye, Man, Yan-Gao, Ouchi, Mutsuko, Ouchi, Toru, Deng, Chu-Xia
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.11.2010; Nature Publishing Group
• Subjects: 631/208/176/1968; 631/208/176/1988; 631/208/200; 692/699/67/1347; Animal models; Animals; Biomedical and Life Sciences; BRCA1; BRCA1 protein; BRCA1 Protein - genetics; BRCA1 Protein - metabolism; BRCA1 Protein - physiology; Breast cancer; Breast Neoplasms - enzymology; Breast Neoplasms - metabolism; c-Fos protein; c-Myc protein; Cell Biology; Cell Line, Tumor; Chromatin; CpG Islands; CpG岛; Deoxyribonucleic acid; DNA; DNA (Cytosine-5-)-Methyltransferase 1; DNA (Cytosine-5-)-Methyltransferases - genetics; DNA (Cytosine-5-)-Methyltransferases - metabolism; DNA Methylation; DNA甲基化; Dnmt1 gene; DNMT1 protein; Enzymes; Epithelial cells; Female; Gene Expression Regulation, Neoplastic; Genomic Imprinting; Histones - metabolism; Humans; Islands; Life Sciences; Mammary gland; Mammary Glands, Animal - cytology; Mammary Glands, Animal - metabolism; Mice; Octamer Transcription Factor-1 - metabolism; original-article; Promoter Regions, Genetic; Promoters; Protein Binding; Proto-Oncogene Proteins c-fos - genetics; Proto-Oncogene Proteins c-fos - metabolism; Proto-Oncogene Proteins c-myc - genetics; Proto-Oncogene Proteins c-myc - metabolism; Proto-Oncogene Proteins p21(ras) - genetics; Proto-Oncogene Proteins p21(ras) - metabolism; Transcription; Transcriptional Activation; Tumors; 乳腺上皮细胞; 基因转录; 小鼠模型; 机制转变; 表达调控; DNA methylation; DNMT1; tumor formation; BRCA1; genomic imprinting; histone modification
• ISSN: 1001-0602; 1748-7838
• DOI: 10.1038/cr.2010.128

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 BRCAl-associated breast cancer formation.