title: Dioxin induces Ahr-dependent robust DNA demethylation of the Cyp1a1 promoter via Tdg in the mouse liver.
abstract: The aryl hydrocarbon receptor (Ahr) is a highly conserved nuclear receptor that plays an important role in the manifestation of toxicity induced by polycyclic aromatic hydrocarbons. As a xenobiotic sensor, Ahr is involved in chemical biotransformation through activation of drug metabolizing enzymes. The activated Ahr cooperates with coactivator complexes to induce epigenetic modifications at target genes. Thus, it is conceivable that 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a potent Ahr ligand, may elicit robust epigenetic changes in vivo at the Ahr target gene cytochrome P450 1a1 (Cyp1a1). A single dose of TCDD administered to adult mice induced Ahr-dependent CpG hypomethylation, changes in histone modifications, and thymine DNA glycosylase (Tdg) recruitment at the Cyp1a1 promoter in the liver within 24 hrs. These epigenetic changes persisted until 40 days post-TCDD treatment and there was Cyp1a1 mRNA hyperinduction upon repeat administration of TCDD at this time-point. Our demethylation assay using siRNA knockdown and an in vitro methylated plasmid showed that Ahr, Tdg, and the ten-eleven translocation methyldioxygenases Tet2 and Tet3 are required for the TCDD-induced DNA demethylation. These results provide novel evidence of Ahr-driven active DNA demethylation and epigenetic memory. The epigenetic alterations influence response to subsequent chemical exposure and imply an adaptive mechanism to xenobiotic stress.
authors.affiliation: Laboratory of Environmental Health Sciences, Center for Disease Biology and Integrative Medicine, Graduate School and Faculty of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Hesbon Z
authors.initials: HZ
authors.lastname: Amenya
authors.affiliation: Laboratory of Environmental Health Sciences, Center for Disease Biology and Integrative Medicine, Graduate School and Faculty of Medicine, The University of Tokyo, Tokyo, Japan.|Experimental Biology Laboratory, Faculty of Medicine, University of Tsukuba, Tsukuba 305-8575, Japan.
authors.forename: Chiharu
authors.initials: C
authors.lastname: Tohyama
authors.affiliation: Laboratory of Environmental Health Sciences, Center for Disease Biology and Integrative Medicine, Graduate School and Faculty of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Seiichiroh
authors.initials: S
authors.lastname: Ohsako
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D018899:CpG Islands; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics*; D000073399:DNA Demethylation / Q000187:drug effects*; D004785:Environmental Pollutants / Q000633:toxicity; D005260:Female; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity*; D011401:Promoter Regions, Genetic / Q000187:drug effects; D018336:Receptors, Aryl Hydrocarbon / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D044502:Thymine DNA Glycosylase / Q000378:metabolism*
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D019363:Cytochrome P-450 CYP1A1; D004785:Environmental Pollutants; D000072317:Polychlorinated Dibenzodioxins; D018336:Receptors, Aryl Hydrocarbon; D044502:Thymine DNA Glycosylase; C484722:Ahr protein, mouse