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ToxSci Advance Access published online on July 2, 2009
Toxicological Sciences, doi:10.1093/toxsci/kfp144
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© The Author 2009. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org

Dioxin increases the interaction between aryl hydrocarbon receptor and estrogen receptor alpha at human promoters

Shaimaa Ahmed*, Eivind Valen{dagger}, Albin Sandelin{dagger} and Jason Matthews*

* Department of Pharmacology & Toxicology, University of Toronto, Toronto, Ontario, Canada M5S 1A8 {dagger} The Bioinformatics Centre, Department of Biology & Biotech Research and Innovation Centre, University of Copenhagen, Denmark

Address correspondence to: Jason Matthews, Ph.D., University of Toronto, Department of Pharmacology & Toxicology, Medical Sciences Building, Room 4336, 1 King's College Circle, Toronto, ON Canada, M5S 1A8, Phone: 416-946-0852, Fax: 416-978-2723, E-mail: jason.matthews{at}utoronto.ca

Received May 19, 2009; revision received June 26, 2009; accepted June 27, 2009


  Abstract

Recent studies have shown that activated aryl hydrocarbon receptor (AHR) induced the recruitment of estrogen receptor {alpha} (ER{alpha}) to AHR-regulated genes and that AHR is recruited to ER{alpha}-regulated genes. However, these findings were limited to a small number of well characterized AHR or ER{alpha} responsive genes with little knowledge of what was occurring at other genomic regions. In this study we showed using chromatin immunoprecipitation followed by hybridization to promoter focused microarrays (ChIP-chip) that 2,3,7,8 -tetrachlorodibenzo–p-dioxin (TCDD) treatment significantly increased the overlap of genomic regions bound by both AHR and ER{alpha}. Conventional and sequential ChIPs confirmed the recruitment of AHR and ER{alpha} to many of the identified regions. Transcription factor binding site analysis revealed an over-representation of AHREs (AHR response elements) in regions bound by both AHR and ER{alpha}, suggesting that AHR was the important factor determining the recruitment of ER{alpha} to these regions. RNAi-mediated knockdown of AHR confirmed its requirement for the recruitment of ER{alpha} to some, but not all, of the shared regions. Our findings demonstrate that dioxin induces the recruitment of ER{alpha} to AHR target genes but also that AHR is recruited to estrogen responsive regions in a gene-specific manner, suggesting that AHR utilizes both of these mechanisms to modulate estrogen dependent signaling.

Key Words: aryl hydrocarbon receptor; estrogen receptor {alpha}; ChIP-chip; receptor crosstalk; dioxin.


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