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首页> 外文期刊>Archives of Toxicology >From transient transcriptome responses to disturbed neurodevelopment: Role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects
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From transient transcriptome responses to disturbed neurodevelopment: Role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects

机译：从短暂的转录组反应到神经发育受阻：组蛋白乙酰化和甲基化在可逆和不可逆药物作用之间的表观遗传转换中的作用

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The superordinate principles governing the transcriptome response of differentiating cells exposed to drugs are still unclear. Often, it is assumed that toxicogenomics data reflect the immediate mode of action (MoA) of drugs. Alternatively, transcriptome changes could describe altered differentiation states as indirect consequence of drug exposure. We used here the developmental toxicants valproate and trichostatin A to address this question. Neurally differentiating human embryonic stem cells were treated for 6 days. Histone acetylation (primary MoA) increased quickly and returned to baseline after 48 h. Histone H3 lysine methylation at the promoter of the neurodevelopmental regulators PAX6 or OTX2 was increasingly altered over time. Methylation changes remained persistent and correlated with neurodevelopmental defects and with effects on PAX6 gene expression, also when the drug was washed out after 3-4 days. We hypothesized that drug exposures altering only acetylation would lead to reversible transcriptome changes (indicating MoA), and challenges that altered methylation would lead to irreversible developmental disturbances. Data from pulse-chase experiments corroborated this assumption. Short drug treatment triggered reversible transcriptome changes; longer exposure disrupted neurodevelopment. The disturbed differentiation was reflected by an altered transcriptome pattern, and the observed changes were similar when the drug was washed out during the last 48 h. We conclude that transcriptome data after prolonged chemical stress of differentiating cells mainly reflect the altered developmental stage of the model system and not the drug MoA. We suggest that brief exposures, followed by immediate analysis, are more suitable for information on immediate drug responses and the toxicity MoA.
机译：尚不清楚控制暴露于药物的分化细胞的转录组应答的上位原理。通常，假设毒理基因组学数据反映了药物的即时作用方式（MoA）。另外，转录组的变化可能描述了分化状态的改变是药物暴露的间接结果。我们在这里使用了有毒的丙戊酸盐和曲古抑菌素A来解决这个问题。将神经分化的人胚胎干细胞处理6天。组蛋白乙酰化（主要MoA）迅速增加，并在48小时后恢复到基线。神经发育调节剂PAX6或OTX2的启动子处的组蛋白H3赖氨酸甲基化随时间而变化。甲基化变化仍然持续存在，并且与神经发育缺陷以及对PAX6基因表达的影响相关，当药物在3-4天后被冲洗掉时也是如此。我们假设仅改变乙酰化的药物暴露会导致可逆的转录组变化（表明MoA），而改变甲基化的挑战将导致不可逆的发育障碍。来自脉冲追踪实验的数据证实了这一假设。短期药物治疗触发可逆的转录组变化;长时间接触会破坏神经发育。转录组模式的改变反映了分化的紊乱，并且在最后48小时内冲洗掉药物时观察到的变化是相似的。我们得出结论，分化细胞长时间受到化学应激后的转录组数据主要反映了模型系统发育阶段的改变，而不是药物MoA。我们建议短暂接触，然后立即分析，更适合即时药物反应和毒性MoA的信息。

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