title: Estrogen receptor α can selectively repress dioxin receptor-mediated gene expression by targeting DNA methylation.
abstract: Selective inhibitory crosstalk has been known to occur within the signaling pathways of the dioxin (AhR) and estrogen (ERα) receptors. More specifically, ERα represses a cytochrome P450-encoding gene (CYP1A1) that converts cellular estradiol into a metabolite that inhibits the cell cycle, while it has no effect on a P450-encoding gene (CYP1B1) that converts estrodiol into a genotoxic product. Here we show that ERα represses CYP1A1 by targeting the Dnmt3B DNA methyltransferase and concomitant DNA methylation of the promoter. We also find that histone H2A.Z can positively contribute to CYP1A1 gene expression, and its presence at that gene is inversely correlated with DNA methylation. Taken together, our results provide a framework for how ERα can repress transcription, and how that impinges on the production of an enzyme that generates genotoxic estradiol metabolites, and potential breast cancer progression. Finally, our results reveal a new mechanism for how H2A.Z can positively influence gene expression, which is by potentially competing with DNA methylation events in breast cancer cells.
authors.affiliation: Département de biologie, Faculté des sciences, Université de Sherbrooke, Sherbrooke, Québec J1K 2R1, Canada.
authors.forename: Maud
authors.initials: M
authors.lastname: Marques
authors.forename: Liette
authors.initials: L
authors.lastname: Laflamme
authors.forename: Luc
authors.initials: L
authors.lastname: Gaudreau
mesh_terms: D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics; D002460:Cell Line; D019363:Cytochrome P-450 CYP1A1 / Q000096:biosynthesis / Q000235:genetics*; D065633:Cytochrome P-450 CYP1B1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000378:metabolism / Q000502:physiology; D019175:DNA Methylation / Q000187:drug effects; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D005786:Gene Expression Regulation; D006657:Histones / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D061986:MCF-7 Cells; D000072317:Polychlorinated Dibenzodioxins / Q000494:pharmacology; D011401:Promoter Regions, Genetic; D018336:Receptors, Aryl Hydrocarbon / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism*; D000097584:DNA Methyltransferase 3B
chemical_list: D001189:Aryl Hydrocarbon Hydroxylases; D019363:Cytochrome P-450 CYP1A1; D065633:Cytochrome P-450 CYP1B1; D004248:DNA (Cytosine-5-)-Methyltransferases; D047628:Estrogen Receptor alpha; D006657:Histones; D000072317:Polychlorinated Dibenzodioxins; D018336:Receptors, Aryl Hydrocarbon; D012097:Repressor Proteins; D000097584:DNA Methyltransferase 3B; C077020:histone H2A.F-Z; C585496:CYP1B1 protein, human