Genome-wide analysis of estrogen receptor binding sites

Abstract

The estrogen receptor is the master transcriptional regulator of breast cancer phenotype and the archetype of a molecular therapeutic target. We mapped all estrogen receptor and RNA polymerase II binding sites on a genome-wide scale, identifying the authentic cis binding sites and target genes, in breast cancer cells. Combining this unique resource with gene expression data demonstrates distinct temporal mechanisms of estrogen-mediated gene regulation, particularly in the case of estrogen-suppressed genes. Furthermore, this resource has allowed the identification of cis-regulatory sites in previously unexplored regions of the genome and the cooperating transcription factors underlying estrogen signaling in breast cancer.

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Figure 1: Summary of estrogen receptor and RNA PolII binding sites and correlation with nucleotide and gene number.
Figure 2: Estrogen-mediated transcript changes and correlation with estrogen receptor binding.
Figure 3: Estrogen receptor and RNA PolII binding relative to specific gene targets.
Figure 4: Identification of enriched motifs within the estrogen receptor binding sites and validation of transcription factor binding.
Figure 5: Involvement of cooperating transcription factors at estrogen receptor binding sites.
Figure 6: The role of NRIP1 in mediating gene repression.
Figure 7: Assessment of estrogen receptor binding properties in different cell systems.

Change history

  • 20 October 2006

    In the version of this article initially published online, the estrogen receptor and RNA PolII binding data were aligned incorrectly in the top panel of Figure 3, which represents estrogen receptor binding at the ESR1 gene region. In addition, a reference to a website containing reference data files was omitted from the main text and Supplementary Note. This URL has been added to the Methods section and the Supplementary Note replaced. These errors have been corrected for all versions of the article

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Acknowledgements

The authors would like to thank D. Lynch, M. Lupien, M. Laza and O. Jänne for helpful discussions and review of the manuscript. This work was supported by grants from the US National Institute of Diabetes and Digestive and Kidney Diseases (DK074967) and the US National Cancer Institute–sponsored Dana-Farber/Harvard Cancer Center Breast Cancer SPORE Grant (CA089393); by the Claudia Adams Barr Program in Innovative Basic Cancer Research (M.B., P.A.S., X.S.L.); by US Department of Defense Breast Cancer Research Program Awards (M.B., J.S.C.) and by fellowships from the Fondation Recherche Medicale (J.E.), the Susan G. Komen Breast Cancer Foundation (E.K.K.) and the US National Institutes of Health (T.R.G. and C.A.M.).

Author information

This study was designed by J.S.C., C.A.M., A.S.B., P.A.S., X.S.L., T.R.G. and M.B. The experimental procedures were performed by J.S.C., with assistance in specific areas from T.R.G., J.E., E.K.K., K.C.F. and Q.W. Biostatistical support was provided by C.A.M., J.S., W.L. and X.S.L. Microarray support and analysis was provided by G.F.H., S.B., V.S., E.A.F. and T.R.G.

Correspondence to X Shirley Liu or Myles Brown.

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Competing interests

T.R. Gingeras is an employee of Affymetrix, Inc.

Supplementary information

Supplementary Fig. 1

Validation of ER binding sites adjacent to estrogen target genes. (PDF 41 kb)

Supplementary Fig. 2

Assessment of mechanisms of early and late gene repression. (PDF 100 kb)

Supplementary Fig. 3

Pairwise analysis of motifs at different cutoff scores. (PDF 61 kb)

Supplementary Table 1

ER binding at previously characterized putative ER binding sites. (PDF 76 kb)

Supplementary Table 2

Enriched motifs within ER binding sites. (PDF 42 kb)

Supplementary Table 3

Primer sequences. (PDF 48 kb)

Supplementary Note (PDF 37 kb)

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Carroll, J., Meyer, C., Song, J. et al. Genome-wide analysis of estrogen receptor binding sites. Nat Genet 38, 1289–1297 (2006) doi:10.1038/ng1901

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