BRCA1 affects global DNA methylation through regulation of DNMT1

Vivek Shukla, Xavier Coumoul, Tyler Lahusen, Rui Hong Wang, Xiaoling Xu, Athanassios Vassilopoulos, Cuiying Xiao, Mi Hye Lee, Yan Gao Man, Mutsuko Ouchi, Toru Ouchi, Chu Xia Deng*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

62 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1201-1215
Number of pages15
JournalCell Research
Volume20
Issue number11
DOIs
StatePublished - Nov 2010

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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