Mechanism of dioxin action: Ah receptor-mediated increase in promoter accessibility in vivo.
We have analyzed dioxin-inducible, Ah receptor-dependent changes in protein-DNA interactions at the CYP1A1 transcriptional promoter in intact mouse hepatoma cells. Our findings indicate that in uninduced cells, the promoter is inaccessible to its cognate binding proteins, which are known to be expressed constitutively. Dioxin induces, in Ah receptor-dependent fashion, an increase in promoter accessibility, which occurs rapidly and does not require ongoing transcription of the CYP1A1 gene. The change in promoter accessibility is not due to an altered pattern of cytosine methylation at the promoter; it probably reflects a 2,3,7,8-tetrachlorodibenzo-p-dioxin- induced change in the chromatin structure. These findings provide new insight into the mechanism of dioxin action and contribute to a better understanding of the regulation of inducible gene transcription in mammalian cells.
Wu
L
L
Department of Pharmacology, Stanford University School of Medicine, CA 94305-5332.
Whitlock
J P
JP
D000818:Animals; D001483:Base Sequence; D001579:Benzopyrene Hydroxylase / Q000235:genetics*; D004247:DNA / Q000737:chemistry; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004742:Enhancer Elements, Genetic; D005786:Gene Expression Regulation / Q000187:drug effects; D066298:In Vitro Techniques; D008114:Liver Neoplasms, Experimental; D008745:Methylation; D051379:Mice; D008969:Molecular Sequence Data; D009838:Oligodeoxyribonucleotides / Q000737:chemistry; D000072317:Polychlorinated Dibenzodioxins / Q000494:pharmacology*; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D012333:RNA, Messenger / Q000235:genetics; D018336:Receptors, Aryl Hydrocarbon; D011955:Receptors, Drug / Q000502:physiology*; D012045:Regulatory Sequences, Nucleic Acid; D014158:Transcription, Genetic / Q000187:drug effects; D014407:Tumor Cells, Cultured
D004268:DNA-Binding Proteins; D009838:Oligodeoxyribonucleotides; D000072317:Polychlorinated Dibenzodioxins; D012333:RNA, Messenger; D018336:Receptors, Aryl Hydrocarbon; D011955:Receptors, Drug; D004247:DNA; D001579:Benzopyrene Hydroxylase