Aryl Hydrocarbon Receptor Modulation of Estrogen Receptor α-Mediated Gene Regulation by a Multimeric Chromatin Complex Involving the Two Receptors and the Coregulator RIP140

Nov 11, 2011Toxicological sciences : an official journal of the Society of Toxicology

How the Aryl Hydrocarbon Receptor Influences Estrogen Receptor Alpha's Gene Control Through a Protein Complex Including Both Receptors and RIP140

AI simplified

Circadian Biology on OpenScience ↗PubMed ↗DOI ↗

Abstract

AhR knockdown increased the expression of ERα-mediated genes upon E2 treatment.

AhR and ERα interact at gene regulatory sites, influencing gene transcription in breast cancer cells.
Gene regulations were categorized as E2-responsive, dioxin-responsive, or responsive to both ligands.
RIP140 was found to play coactivator or corepressor roles depending on ERα's presence at gene regulatory sites.
E2 and dioxin promoted the formation of a complex involving ERα, AhR, and RIP140 at specific gene sites.
AhR modulates ERα-mediated gene stimulation by altering RIP140 recruitment to these regulatory regions.

AI simplified

Although crosstalk between aryl hydrocarbon receptor (AhR) and estrogen receptor α (ERα) is well established, the mechanistic basis and involvement of other proteins in this process are not known. Because we observed an enrichment of AhR-binding motifs in ERα-binding sites of many estradiol (E2)-regulated genes, we investigated how AhR might modulate ERα-mediated gene transcription in breast cancer cells. Gene regulations were categorized based on their pattern of stimulation by E2 and/or dioxin and were denoted E2-responsive, dioxin-responsive, or responsive to either ligand. ERα, AhR, aryl hydrocarbon receptor translocator, and receptor interacting protein 140 (RIP140) were recruited to gene regulatory regions in a gene-specific and E2/dioxin ligand-specific manner. Knockdown of AhR markedly increased the expression of ERα-mediated genes upon E2 treatment. This was not attributable to a change in ERα level, or recruitment of ERα, phosphoSer5-RNA Pol II, or several coregulators but rather was associated with greatly diminished recruitment of the coregulator RIP140 to gene regulatory sites. Changing the cellular level of RIP140 revealed coactivator or corepressor roles for this coregulator in E2- and dioxin-mediated gene regulation, the choice of which was determined by the presence or absence of ERα at gene regulatory sites. Coimmunoprecipitation and chromatin immunoprecipitation (ChIP)-reChIP studies documented that E2- or dioxin-promoted formation of a multimeric complex of ERα, AhR, and RIP140 at ERα-binding sites of genes regulated by either E2 or dioxin. Our findings highlight the importance of cross-regulation between AhR and ERα and a novel mechanism by which AhR controls, through modulating the recruitment of RIP140 to ERα-binding sites, the kinetics and magnitude of ERα-mediated gene stimulation.

Full Text

Full text is available at the source.

View full text ↗

Aryl Hydrocarbon Receptor Modulation of Estrogen Receptor α-Mediated Gene Regulation by a Multimeric Chromatin Complex Involving the Two Receptors and the Coregulator RIP140

Abstract

Full Text

You found one interesting study. We’ll send the next 7.

what lands in your inbox each week:

Recent issues from the circadian biology brief