Volume 20, No 11, Nov 2010
ISSN: 1001-0602
EISSN: 1748-7838 2018
impact factor 17.848*
(Clarivate Analytics, 2019)
Volume 20 Issue 11, November 2010: 1201-1215
ORIGINAL ARTICLES
BRCA1 affects global DNA methylation through regulation of DNMT1
Vivek Shukla1,4,*, Xavier Coumoul1,5,*, Tyler Lahusen1, Rui-Hong Wang1, Xiaoling Xu1, Athanassios Vassilopoulos1, Cuiying Xiao1, Mi-Hye Lee1, Yan-Gao Man2, Mutsuko Ouchi3, Toru Ouchi3 and Chu-Xia Deng1
1Genetics of Development and Disease Branch, 10/9N105, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA
2Department of Gynecologic and Breast Pathology, Armed Forces Institute of Pathology and American Registry of Pathology, Washington, DC 20306, USA
3Department of Medicine, NUHS, Pritzker School of Medicine, The University of Chicago, Evanston, IL 60201, USA
4Present address: Department of Gastroenterology, Hepatology and Nutrition, Unit 1466, MD Anderson Cancer Center, University of Texas, 1400 Pressler Street, Houston, TX 77030-3722, USA
5present address: INSERM UMR-S 747, Unite de Pharmacologie, Toxicologie et Signalisation Cellulaire, Centre Universitaire des Saints-P鑢es, 45 rue des Saints-Peres 75006 Paris, France
Correspondence: Chu-Xia Deng,(chuxiad@bdg10.niddk.nih.gov)
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.
Cell Research (2010) 20:1201-1215. doi:10.1038/cr.2010.128; published online 7 September 2010
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