Dioxin increases the interaction between aryl hydrocarbon receptor and estrogen receptor alpha at human promoters.
Recent studies have shown that activated aryl hydrocarbon receptor (AHR) induced the recruitment of estrogen receptor-alpha (ERalpha) to AHR-regulated genes and that AHR is recruited to ERalpha-regulated genes. However, these findings were limited to a small number of well-characterized AHR- or ERalpha-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 treatment significantly increased the overlap of genomic regions bound by both AHR and ERalpha. Conventional and sequential ChIPs confirmed the recruitment of AHR and ERalpha to many of the identified regions. Transcription factor binding site analysis revealed an overrepresentation of aryl hydrocarbon receptor response elements in regions bound by both AHR and ERalpha, suggesting that AHR was the important factor determining the recruitment of ERalpha to these regions. RNA interference-mediated knockdown of AHR confirmed its requirement for the recruitment of ERalpha to some, but not all, of the shared regions. Our findings demonstrate not only that dioxin induces the recruitment of ERalpha 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.
Ahmed
Shaimaa
S
Department of Pharmacology & Toxicology, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
Valen
Eivind
E
Sandelin
Albin
A
Matthews
Jason
J
D001483:Base Sequence; D015153:Blotting, Western; D017931:DNA Primers; D004147:Dioxins / Q000633:toxicity*; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D006801:Humans; D009693:Nucleic Acid Hybridization; D016133:Polymerase Chain Reaction; D018336:Receptors, Aryl Hydrocarbon / Q000378:metabolism*
D017931:DNA Primers; D004147:Dioxins; D047628:Estrogen Receptor alpha; D018336:Receptors, Aryl Hydrocarbon