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Genome-wide mapping of estrogen receptor-beta-binding regions reveals extensive cross-talk with transcription factor activator protein-1.

Abstract
Estrogen signaling can occur through a nonclassical pathway involving the interaction of estrogen receptors (ER) with other transcription factors such as activator protein-1 (AP-1) and SP-1. However, there is little mechanistic understanding about this pathway, with conflicting results from in vitro investigations. In this study, we applied the ChIP-on-chip approach to identify ERbeta-binding sites on a genome-wide scale, identifying 1,457 high-confidence binding sites in ERbeta-overexpressing MCF7 breast cancer cells. Genes containing ERbeta-binding sites can be regulated by E2. Notably, approximately 60% of the genomic regions bound by ERbeta contained AP-1-like binding regions and estrogen response element-like sites, suggesting a functional association between AP-1 and ERbeta signaling. Chromatin immunoprecipitation (ChIP) analysis confirmed the association of AP-1, which is composed of the oncogenic transcription factors c-Fos and c-Jun, to ERbeta-bound DNA regions. Using a re-ChIP assay, we showed co-occupancy of ERbeta and AP-1 on chromatin. Short interfering RNA-mediated knockdown of c-Fos or c-Jun expression decreased ERbeta recruitment to chromatin, consistent with the role of AP-1 in mediating estrogen signaling in breast cancer cells. Additionally, ERalpha and ERbeta recruitment to AP-1/ERbeta target regions exhibited gene-dependent differences in response to antiestrogens. Together, our results broaden insights into ERbeta DNA-binding at the genomic level by revealing crosstalk with the AP-1 transcription factor.
AuthorsChunyan Zhao, Hui Gao, Yawen Liu, Zoi Papoutsi, Sadaf Jaffrey, Jan-Ake Gustafsson, Karin Dahlman-Wright
JournalCancer research (Cancer Res) Vol. 70 Issue 12 Pg. 5174-83 (Jun 15 2010) ISSN: 1538-7445 [Electronic] United States
PMID20501845 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Chromatin
  • Estrogen Receptor beta
  • Estrogens
  • RNA, Messenger
  • Transcription Factor AP-1
  • Luciferases
Topics
  • Blotting, Western
  • Breast Neoplasms (genetics, metabolism, pathology)
  • Cell Line, Tumor
  • Cell Proliferation
  • Chromatin (metabolism)
  • Chromatin Immunoprecipitation
  • Estrogen Receptor beta (genetics, metabolism)
  • Estrogens (pharmacology)
  • Female
  • Genome, Human
  • Humans
  • Luciferases (metabolism)
  • Promoter Regions, Genetic (genetics)
  • RNA, Messenger (genetics, metabolism)
  • Response Elements (genetics)
  • Reverse Transcriptase Polymerase Chain Reaction
  • Transcription Factor AP-1 (genetics, metabolism)

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