Dose-dependent alcohol-induced alterations in chromatin structure persist beyond the window of exposure and correlate with fetal alcohol syndrome birth defects.
Dose-dependent alcohol-induced alterations in chromatin structure persist beyond the window of exposure and correlate with fetal alcohol syndrome birth defects.
复制标题
剂量依赖性酒精诱导的染色质结构的改变持续到暴露窗口，并与胎儿酒精综合征的先天缺陷相关。
DOI：
10.1186/s13072-015-0031-7
复制
发表时间：
2015
影响因子：
3.9
通讯作者：
Golding MC
中科院分区：
文献类型：
--
作者：
Veazey KJ;Parnell SE;Miranda RC;Golding MC
近年来，我们已经认识到，大量的宫内暴露有能力诱导先天性和代谢缺陷的发展。由于大多数这些遭遇表现出他们的影响超出了暴露的窗口，破译致畸机制是令人难以置信的困难。对于许多代理人来说，改变的表观遗传编程已成为可疑的传播持久的签名暴露导致发育不良。然而，虽然有几种化学物质可以严重干扰染色质结构，但对于许多试剂（特别是酒精），尚不清楚这些修饰是否代表对暴露或导致病理学的遗传性病变的短暂反应。在这里，我们报告说，小鼠遇到急性暴露于酒精在妊娠第7天表现出显着的变化，染色质结构（组蛋白3赖氨酸9二甲基化，赖氨酸9乙酰化，赖氨酸27三甲基化）在第17天，这些变化与颅面和中枢神经系统缺陷的发展密切相关。使用神经皮质干细胞模型，我们发现，酒精暴露的结果所产生的表观遗传变化在很大程度上取决于所调查的基因，酒精的剂量遇到的，和所产生的签名明显不同于4天的恢复期后所观察到的。重要的是，恢复后观察到的变化与体内建模的变化一致，并且与编码指导神经发生的多个同源框基因的转录物的改变相关。出乎意料的是，我们没有观察到酒精诱导的染色质结构变化和转录改变之间的相关性。有趣的是，观察到的大多数表观遗传变化发生在与抑制性染色质结构相关的标记中，我们在编码Dnmt 1，Eed，Ehmt 2（G9 a），EzH 2，Kdm 1a，Kdm 4c，Setdb 1，Sod 3，Tet 1和Uhrf 1的转录物中鉴定了相关的破坏。这些观察结果表明，酒精暴露对染色质结构的直接和长期影响是不同的，并暗示在开发过程中可能存在协调的表观遗传反应乙醇。总的来说，我们的研究结果表明，酒精诱导的染色质结构的修改持续超出窗口的曝光，并可能有助于胎儿酒精综合征相关的先天性异常的发展。本文的在线版本（doi：10.1186/s13072-015-0031-7）包含补充材料，可供授权用户使用。
In recent years, we have come to recognize that a multitude of in utero exposures have the capacity to induce the development of congenital and metabolic defects. As most of these encounters manifest their effects beyond the window of exposure, deciphering the mechanisms of teratogenesis is incredibly difficult. For many agents, altered epigenetic programming has become suspect in transmitting the lasting signature of exposure leading to dysgenesis. However, while several chemicals can perturb chromatin structure acutely, for many agents (particularly alcohol) it remains unclear if these modifications represent transient responses to exposure or heritable lesions leading to pathology. Here, we report that mice encountering an acute exposure to alcohol on gestational Day-7 exhibit significant alterations in chromatin structure (histone 3 lysine 9 dimethylation, lysine 9 acetylation, and lysine 27 trimethylation) at Day-17, and that these changes strongly correlate with the development of craniofacial and central nervous system defects. Using a neural cortical stem cell model, we find that the epigenetic changes arising as a consequence of alcohol exposure are heavily dependent on the gene under investigation, the dose of alcohol encountered, and that the signatures arising acutely differ significantly from those observed after a 4-day recovery period. Importantly, the changes observed post-recovery are consistent with those modeled in vivo, and associate with alterations in transcripts encoding multiple homeobox genes directing neurogenesis. Unexpectedly, we do not observe a correlation between alcohol-induced changes in chromatin structure and alterations in transcription. Interestingly, the majority of epigenetic changes observed occur in marks associated with repressive chromatin structure, and we identify correlative disruptions in transcripts encoding Dnmt1, Eed, Ehmt2 (G9a), EzH2, Kdm1a, Kdm4c, Setdb1, Sod3, Tet1 and Uhrf1. These observations suggest that the immediate and long-term impacts of alcohol exposure on chromatin structure are distinct, and hint at the existence of a possible coordinated epigenetic response to ethanol during development. Collectively, our results indicate that alcohol-induced modifications to chromatin structure persist beyond the window of exposure, and likely contribute to the development of fetal alcohol syndrome-associated congenital abnormalities. The online version of this article (doi:10.1186/s13072-015-0031-7) contains supplementary material, which is available to authorized users.