From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects.
From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects.
复制标题
DOI：
10.1007/s00204-014-1279-6
复制
发表时间：
2014-07
影响因子：
6.1
通讯作者：
Leist, Marcel
中科院分区：
文献类型：
--
作者：
Balmer, Nina V.;Klima, Stefanie;Rempel, Eugen;Ivanova, Violeta N.;Kolde, Raivo;Weng, Matthias K.;Meganathan, Kesavan;Henry, Margit;Sachinidis, Agapios;Berthold, Michael R.;Hengstler, Jan G.;Rahnenfuhrer, Jorg;Waldmann, Tanja;Leist, Marcel
调控暴露于药物的分化细胞转录组反应的上位原则仍不明确。通常认为，毒理基因组学数据反映药物的直接作用模式（MoA）。或者，转录组变化可能描述作为药物暴露间接后果的分化状态改变。我们在此使用发育毒物丙戊酸盐和曲古抑菌素A来解决这个问题。神经分化的人类胚胎干细胞处理6天。组蛋白乙酰化（主要作用模式）迅速增加，并在48小时后恢复到基线。神经发育调节因子PAX6或OTX2启动子处的组蛋白H3赖氨酸甲基化随时间推移逐渐改变。甲基化变化持续存在，并与神经发育缺陷以及对PAX6基因表达的影响相关，即使在药物作用3 - 4天后被洗脱也是如此。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（表明作用模式），而改变甲基化的刺激会导致不可逆的发育紊乱。脉冲追踪实验的数据证实了这一假设。短期药物处理引发可逆的转录组变化；较长时间的暴露破坏神经发育。分化紊乱反映在转录组模式的改变上，并且当药物在最后48小时内被洗脱时，观察到的变化相似。我们得出结论，分化细胞长期受到化学应激后的转录组数据主要反映模型系统的发育阶段改变，而非药物作用模式。我们建议，短暂暴露后立即分析更适合获取有关药物即时反应和毒性作用模式的信息。
本文的在线版本（doi:10.1007/s00204 - 014 - 1279 - 6）包含补充材料，授权用户可获取。
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. The online version of this article (doi:10.1007/s00204-014-1279-6) contains supplementary material, which is available to authorized users.
登录
查看更多内容
影响因子：
4.2
作者：
Fass, Daniel M.;Shah, Rishita;Ghosh, Balaram;Hennig, Krista;Norton, Stephanie;Zhao, Wen-Ning;Reis, Surya A.;Klein, Peter S.;Mazitschek, Ralph;Maglathlin, Rebecca L.;Lewis, Timothy A.;Haggarty, Stephen J.
通讯作者：
Haggarty, Stephen J.
影响因子：
4.8
作者：
Hezroni, Hadas;Sailaja, Badi Sri;Meshorer, Eran
通讯作者：
Meshorer, Eran
影响因子：
5.6
作者：
Hartung, Thomas;van Vliet, Erwin;Thomas, Russell
通讯作者：
Thomas, Russell
影响因子：
12.3
作者：
Gentleman RC;Carey VJ;Bates DM;Bolstad B;Dettling M;Dudoit S;Ellis B;Gautier L;Ge Y;Gentry J;Hornik K;Hothorn T;Huber W;Iacus S;Irizarry R;Leisch F;Li C;Maechler M;Rossini AJ;Sawitzki G;Smith C;Smyth G;Tierney L;Yang JY;Zhang J
通讯作者：
Zhang J
影响因子：
9.9
作者：
通讯作者：
--