The potential role of DNA methylation in the response to 2,3,7,8-tetrachlorodibenzo-p-dioxin.
The Ah receptor is an intracellular protein that binds the environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin. The liganded receptor interacts with a specific DNA recognition motif located within a dioxin-responsive enhancer upstream of the CYP1A1 gene. Methylation protection and methylation interference studies indicate that the liganded receptor contacts both DNA strands, at 4 guanine residues contained within the recognition motif. These findings imply that the liganded receptor interacts with its cognate enhancer within the major groove of the DNA helix. Cytosine methylation of the recognition motif at CpG dinucleotides diminishes the protein-DNA interaction, as measured by gel retardation. Furthermore, methylation at cytosine inhibits the enhancer function of the DNA. These findings imply that DNA methylation can diminish the response to dioxin by impeding the Ah receptor-enhancer interaction.
Shen
E S
ES
Department of Pharmacology, Stanford University School of Medicine, California 94305-5332.
Whitlock
J P
JP
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics; D001483:Base Sequence; D002460:Cell Line; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D004273:DNA, Neoplasm / Q000187:drug effects* / Q000378:metabolism; D004147:Dioxins / Q000494:pharmacology*; D004742:Enhancer Elements, Genetic; D005796:Genes; D008114:Liver Neoplasms, Experimental; D008745:Methylation; D051379:Mice; D008969:Molecular Sequence Data; D015345:Oligonucleotide Probes; D010957:Plasmids; D000072317:Polychlorinated Dibenzodioxins / Q000378:metabolism / Q000494:pharmacology*; D018336:Receptors, Aryl Hydrocarbon; D011955:Receptors, Drug / Q000378:metabolism; D014162:Transfection
D004273:DNA, Neoplasm; D004147:Dioxins; D015345:Oligonucleotide Probes; D000072317:Polychlorinated Dibenzodioxins; D018336:Receptors, Aryl Hydrocarbon; D011955:Receptors, Drug; D001189:Aryl Hydrocarbon Hydroxylases