Neonatal activation of the nuclear receptor CAR results in epigenetic memory and permanent change of drug metabolism in mouse liver.
Neonatal activation of the nuclear receptor CAR results in epigenetic memory and permanent change of drug metabolism in mouse liver.
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DOI：
10.1002/hep.25766
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发表时间：
2012-10
期刊：
影响因子：
13.5
通讯作者：
Huang, Wendong
中科院分区：
文献类型：
--
作者：
Chen, Wei-Dong;Fu, Xianghui;Dong, Bingning;Wang, Yan-Dong;Shiah, Steven;Moore, David D.;Huang, Wendong
发育过程中异常的表观遗传改变可能会导致长期的表观遗传记忆，并对受试者的健康产生永久性影响。组成型雄甾烷受体（CAR；NR1I3）是药物/异生物质代谢的中心调节剂。在这里，我们报告了 CAR 的短暂新生儿激活会导致表观遗传记忆和肝脏药物代谢的永久性变化。新生儿暴露于 CAR 特异性配体 1,4-双[2-(3,5-二氯吡啶氧基)]苯 (TCPOBOP) 后，CAR 被激活，导致暴露小鼠一生中持续诱导 CAR 靶基因 Cyp2B10 和 Cyp2C37 的表达。这些小鼠成年后对佐恶唑明治疗的敏感性永久降低。与对照组相比，从这些小鼠分离的肝细胞中 Cyp2B10 和 Cyp2C37 的诱导对低浓度的 CAR 激动剂 TCPOBOP 更敏感。因此，新生儿的 CAR 激活导致 Cyp2B10 位点内组蛋白 3 赖氨酸 4 (H3K4) 单甲基化、二甲基化和三甲基化永久性增加，以及 H3K9 三甲基化减少。转录共激活因子 ASC-2 和组蛋白去甲基酶 JMJD2d 参与了这种 CAR 依赖性表观遗传开关。新生儿 CAR 激活会导致表观遗传记忆和肝脏药物代谢的永久性变化。
Aberrant epigenetic alterations during development may result in long-term epigenetic memory and have a permanent effect on the health of subjects. Constitutive androstane receptor (CAR; NR1I3) is a central regulator of drug/xenobiotic metabolism. Here, we report that transient neonatal activation of CAR results in epigenetic memory and a permanent change of liver drug metabolism. CAR activation by neonatal exposure to a CAR-specific ligand, 1,4-bis[2-(3,5-dichloropyridyloxy)] benzene (TCPOBOP) led to persistently induced expression of the CAR target genes Cyp2B10 and Cyp2C37 throughout the life of exposed mice. These mice showed a permanent reduction in sensitivity to zoxazolamine treatment as adults. Compared with control groups, the induction of Cyp2B10 and Cyp2C37 in hepatocytes isolated from these mice was more sensitive to low concentrations of the CAR agonist TCPOBOP. Accordingly, neonatal activation of CAR led to a permanent increase of histone 3 lysine 4 (H3K4) mono-, di- and trimethylation and decrease of H3K9 trimethylation within the Cyp2B10 locus. Transcriptional coactivator ASC-2 and histone demethylase JMJD2d participated in this CAR-dependent epigenetic switch. Neonatal activation of CAR results in epigenetic memory and a permanent change of liver drug metabolism.
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影响因子：
14.9
作者：
Pornthanakasem, Wichai;Kongruttanachok, Narisorn;Mutirangura, Apiwat
通讯作者：
Mutirangura, Apiwat
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影响因子：
13.5
作者：
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通讯作者：
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影响因子：
13.5
作者：
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通讯作者：
Trumpp, Andreas