Dioxin induces Ahr-dependent robust DNA demethylation of the Cyp1a1 promoter via Tdg in the mouse liver.
Dioxin induces Ahr-dependent robust DNA demethylation of the Cyp1a1 promoter via Tdg in the mouse liver.
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DOI：
10.1038/srep34989
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发表时间：
2016-10-07
影响因子：
4.6
通讯作者：
Ohsako S
中科院分区：
文献类型：
--
作者：
Amenya HZ;Tohyama C;Ohsako S
芳烃受体（Ahr）是一种高度保守的核受体，在多环芳烃引起的毒性表现中发挥着重要作用。作为一种外源传感器，Ahr 通过激活药物代谢酶参与化学生物转化。激活的 Ahr 与共激活剂复合物配合诱导靶基因的表观遗传修饰。因此，可以想象，2,3,7,8-四氯二苯并-对二恶英 (TCDD) 作为一种有效的 Ahr 配体，可能会在 Ahr 靶基因细胞色素 P450 1a1 (Cyp1a1) 处引发体内强烈的表观遗传变化。给予成年小鼠单剂 TCDD，可在 24 小时内诱导 Ahr 依赖性 CpG 低甲基化、组蛋白修饰变化以及肝脏 Cyp1a1 启动子处胸腺嘧啶 DNA 糖基化酶 (Tdg) 的募集。这些表观遗传变化持续到 TCDD 治疗后 40 天，并且在该时间点重复施用 TCDD 后出现 Cyp1a1 mRNA 过度诱导。我们使用 siRNA 敲低和体外甲基化质粒的去甲基化测定表明，Ahr、Tdg 和 10-11 易位甲基双加氧酶 Tet2 和 Tet3 是 TCDD 诱导的 DNA 去甲基化所必需的。这些结果为 Ahr 驱动的主动 DNA 去甲基化和表观遗传记忆提供了新的证据。表观遗传改变影响对随后化学暴露的反应，并暗示对外源胁迫的适应性机制。
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.
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