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Disconnect between alcohol-induced alterations in chromatin structure and gene transcription in a mouse embryonic stem cell model of exposure

机译：在暴露的小鼠胚胎干细胞模型中断开醇诱导的染色质结构和基因转录的变化

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Alterations to chromatin structure induced by environmental insults have become an attractive explanation for the persistence of exposure effects into subsequent life stages. However, a growing body of work examining the epigenetic impact that alcohol and other drugs of abuse exert consistently notes a disconnection between induced changes in chromatin structure and patterns of gene transcription. Thus, an important question is whether perturbations in the 'histone code' induced by prenatal exposures to alcohol implicitly subvert gene expression, or whether the hierarchy of cellular signaling networks driving development is such that they retain control over the transcriptional program. To address this question, we examined the impact of ethanol exposure in mouse embryonic stem cells cultured under 2i conditions, where the transcriptional program is rigidly enforced through the use of small molecule inhibitors. We find that ethanol-induced changes in post-translational histone modifications are dose dependent, unique to the chromatin modification under investigation, and that the extent and direction of the change differ between the period of exposure and the recovery phase. Similar to in vivo models, we find post-translational modifications affecting histone 3 lysine 9 are the most profoundly impacted, with the signature of exposure persisting long after alcohol has been removed. These changes in chromatin structure associate with dose-dependent alterations in the levels of transcripts encoding Dnmt1, Uhrf1, Tet1, Tet2, Tet3, and Polycomb complex members Eed and Ezh2. However, in this model, ethanol-induced changes to the chromatin template do not consistently associate with changes in gene transcription, impede the process of differentiation, or affect the acquisition of monoallelic patterns of expression for the imprinted gene Igf2R. These findings question the inferred universal relevance of epigenetic changes induced by drugs of abuse and suggest that changes in chromatin structure cannot unequivocally explain dysgenesis in isolation. (C) 2017 Elsevier Inc. All rights reserved.
机译：由环境侮辱引起的染色质结构的改变已成为对持续曝光效应持续到后续生命阶段的有吸引力的解释。然而，养成含酒精和其他滥用药物的表观遗传影响的越来越多的工作始终如一地注意到染色蛋白结构和基因转录模式的诱导变化之间的断开。因此，重要的问题是由产前暴露对醇诱导的“组蛋白代码”是否隐含颠覆基因表达的扰动，或者蜂窝信令网络驱动开发的层次是否使得它们保持对转录程序的控制。为了解决这个问题，我们研究了在2I条件下培养的小鼠胚胎干细胞中乙醇暴露的影响，其中通过使用小分子抑制剂刚性强制执行转录程序。我们发现，翻译后组蛋白修饰的乙醇诱导的变化是对染色质修饰的剂量依赖性，并且在调查中是独一无二的，并且变化的范围和方向在暴露期间和回收阶段之间存在差异。类似于体内模型，我们发现影响组蛋白3个赖氨酸9的翻译后修饰是最深刻的影响，随着饮酒后持续长时间持续的曝光签名。染色质结构的这些变化与编码DNMT1，UHRF1，TET1，TET2，TET3和Polycomb复合构件EED和EZH2的转录物的转录物水平的剂量依赖性改变。然而，在该模型中，乙醇诱导的染色质模板的变化与基因转录的变化不一致地赋予分化过程，或者影响用于印迹基因IGF2R的单一的表达模式。这些发现是质疑滥用药物诱导的表观遗传变化的推断普遍相关性，并表明染色质结构的变化不能毫不含糊地解释迟滞的性能。 （c）2017年Elsevier Inc.保留所有权利。

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