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 (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 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 ERa 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 ER alpha, suggesting that AHR was the important factor determining the recruitment of ER(x to these regions. RNA interference-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 not only that dioxin induces the recruitment of ERa 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.