Aryl hydrocarbon receptor drives active demethylation and epigenetic memory at the Cyp1a1 promoter

• AMENYA Hesbon

  Laboratory of Environmental Health Sciences, Faculty of Medicine, The University of Tokyo, Japan

• TOHYAMA Chiharu

  Laboratory of Environmental Health Sciences, Faculty of Medicine, The University of Tokyo, Japan

• OHSAKO Seiichiroh

  Laboratory of Environmental Health Sciences, Faculty of Medicine, The University of Tokyo, Japan

抄録

Ahr activation and downstream signaling may involve epigenetic modulation of target genes. We hypothesized that dioxin, a potent Ahr ligand, may elicit robust epigenetic switching at the Ahr target gene Cyp1a1. We found that TCDD induces Cyp1a1 transcriptional memory in the adult mouse liver. Evidently, there was three-fold super-induction of Cyp1a1 mRNA upon repeat-administration of TCDD, 40 days after the first TCDD dose. TCDD also induced a rapid Cyp1a1 promoter DNA demethylation in Ahr wild-type (Ahr^+/+) but not in Ahr knockout (Ahr^-/-) mice. Increases of H3K4me3 and H4ac as well as loss of H4K20me3 accompanied the Cyp1a1 promoter demethylation. The histone marks and DNA hypomethylation persisted to 40 days post TCDD administration, and constituted epigenetic memorization of the initial TCDD administration. In agreement with an active demethylation mechanism, the methylation loss was coincident with a gradual decrease of 5hmC and association of Tdg with the Cyp1a1 promoter. Similarly, there was a trend of increment of Apex1 and Tet3 binding at the Cyp1a1 promoter, albeit without statistical significance. This trend was observed in TCDD treated Ahr^+/+ mice, but was absent in Ahr^-/- mice. An in vitro demethylation assay utilizing an artificially methylated Cyp1a1 promoter plasmid and siRNA knockdown revealed that Ahr, Tet2, Tet3 and Tdg are required in the initial DNA demethylation. Our study provides novel evidence of nuclear receptor driven epigenetic modulation and memorization. These epigenetic alterations influence response to subsequent chemical exposure and imply an adaptive mechanism to xenobiotic stress.

収録刊行物

• 日本毒性学会学術年会

  日本毒性学会学術年会 43.1 (0), O-48-, 2016

  日本毒性学会

詳細情報

• CRID: 1390282680524013184
• NII論文ID: 130005260648
• DOI: 10.14869/toxpt.43.1.0_o-48
• 本文言語コード: ja
• データソース種別:
  • JaLC
  • CiNii Articles
• 抄録ライセンスフラグ: 使用不可