Disconnect between alcohol-induced alterations in chromatin structure and gene transcription in a mouse embryonic stem cell model of exposure.
Disconnect between alcohol-induced alterations in chromatin structure and gene transcription in a mouse embryonic stem cell model of exposure.
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在小鼠胚胎干细胞暴露模型中，酒精诱导的染色质结构改变与基因转录之间脱节。
DOI：
10.1016/j.alcohol.2017.01.007
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发表时间：
2017
期刊：
影响因子：
--
通讯作者：
Golding,MichaelC
中科院分区：
文献类型：
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作者：
Veazey,KyleeJ;Wang,Haiqing;Bedi,YudhishtarS;Skiles,WilliamM;Chang,RichardCheng-An;Golding,MichaelC
环境损伤引起的染色质结构改变已经成为一种有吸引力的解释，解释了暴露效应在随后的生命阶段的持久性。然而，越来越多的研究酒精和其他药物滥用对表观遗传影响的工作一致指出，染色质结构的诱导变化与基因转录模式之间存在脱节。因此，一个重要的问题是，产前暴露于酒精诱导的“组蛋白密码”的扰动是否会隐性地破坏基因表达，或者驱动发育的细胞信号网络的层次结构是否能够控制转录程序。为了解决这个问题，我们研究了乙醇暴露对2i条件下培养的小鼠胚胎干细胞的影响，在2i条件下，通过使用小分子抑制剂严格执行转录程序。我们发现，乙醇诱导的翻译后组蛋白修饰的变化是剂量依赖性的，是所研究的染色质修饰所特有的，并且这种变化的程度和方向在暴露期和恢复期不同。与体内模型类似，我们发现影响组蛋白3赖氨酸9的翻译后修饰受到的影响最为深远，在酒精被去除后，暴露的特征持续很长时间。这些染色质结构的变化与编码dnmt1、Uhrf1、Tet1、Tet2、Tet3和polycombcomplex成员seedanddezh2的转录本水平的剂量依赖性改变有关。然而，在该模型中，乙醇诱导的染色质模板的变化并不总是与基因转录的变化相关联，也不会阻碍分化过程，也不会影响印迹基因igf2r的单等位基因表达模式的获得。这些发现质疑了药物滥用引起的表观遗传变化的普遍相关性，并表明染色质结构的变化不能明确地单独解释发育不良。
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 toin vivomodels, 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 encodingDnmt1,Uhrf1,Tet1,Tet2,Tet3, andPolycombcomplex membersEedandEzh2.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 geneIgf2R. 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.