Effect of estrogen receptor α binding on functional DNA methylation in breast cancer

Epigenetics. 2014 Apr;9(4):523-32. doi: 10.4161/epi.27688. Epub 2014 Jan 16.

Abstract

Epigenetic modifications introduce an additional layer of regulation that drastically expands the instructional capability of the human genome. The regulatory consequences of DNA methylation is context dependent; it can induce, enhance, and suppress gene expression, or have no effect on gene regulation. Therefore, it is essential to account for the genomic location of its occurrence and the protein factors it associates with to improve our understanding of its function and effects. Here, we use ENCODE ChIP-seq and DNase I hypersensitivity data, along with large-scale breast cancer genomic data from The Cancer Genome Atlas (TCGA) to computationally dissect the intricacies of DNA methylation in regulation of cancer transcriptomes. In particular, we identified a relationship between estrogen receptor α (ERα) activity and DNA methylation patterning in breast cancer. We found compelling evidence that methylation status of DNA sequences at ERα binding sites is tightly coupled with ERα activity. Furthermore, we predicted several transcription factors including FOXA1, GATA1, and SUZ12 to be associated with breast cancer by examining the methylation status of their binding sites in breast cancer. Lastly, we determine that methylated CpGs highly correlated with gene expression are enriched in regions 1kb or more downstream of TSSs, suggesting more significant regulatory roles for CpGs distal to gene TSSs. Our study provides novel insights into the role of ERα in breast cancers.

Keywords: ChIP-seq; DNase I hypersensitivity; breast cancer; differential gene expression; differential methylation; estrogen receptor α; transcription factor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism*
  • CpG Islands
  • DNA Methylation*
  • Estrogen Receptor alpha / genetics
  • Estrogen Receptor alpha / metabolism*
  • Female
  • GATA1 Transcription Factor / genetics
  • Gene Expression Regulation, Neoplastic
  • Genome, Human
  • Hepatocyte Nuclear Factor 3-alpha / genetics
  • Humans
  • Polycomb Repressive Complex 2 / genetics
  • Transcriptome

Substances

  • Estrogen Receptor alpha
  • FOXA1 protein, human
  • GATA1 Transcription Factor
  • GATA1 protein, human
  • Hepatocyte Nuclear Factor 3-alpha
  • SUZ12 protein, human
  • estrogen receptor alpha, human
  • Polycomb Repressive Complex 2