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DNA Methylation program in normal and alcohol-induced thinning cortex

机译：DNA甲基化程序在正常和酒精诱导的皮层中

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While cerebral underdevelopment is a hallmark of fetal alcohol spectrum disorders (FASD), the mechanism(s) guiding the broad cortical neurodevelopmental deficits are not clear. DNA methylation is known to regulate early development and tissue specification through gene regulation. Here, we examined DNA methylation in the onset of alcohol-induced cortical thinning in a mouse model of FASD. C57BL/6 (B6) mice were administered a 4% alcohol (v/v) liquid diet from embryonic (E) days 7-16, and their embryos were harvested at E17, along with isocaloric liquid diet and lab chow controls. Cortical neuroanatomy, neural phenotypes, and epigenetic markers of methylation were assessed using immunohistochemistry, Western blot, and methyl-DNA assays. We report that cortical thickness, neuroepithelial proliferation, and neuronal migration and maturity were found to be deterred by alcohol at E17. Simultaneously, DNA methylation, including 5-methylcytosine (5mC) and 5-hydroxcylmethylcytosine (5hmC), which progresses as an intrinsic program guiding normal embryonic cortical development, was severely affected by in utero alcohol exposure. The intricate relationship between cortical thinning and this DNA methylation program disruption is detailed and illustrated. DNA methylation, dynamic across the multiple cortical layers during the late embryonic stage, is highly disrupted by fetal alcohol exposure; this disruption occurs in tandem with characteristic developmental abnormalities, ranging from structural to molecular. Finally, our findings point to a significant question for future exploration: whether epigenetics guides neurodevelopment or whether developmental conditions dictate epigenetic dynamics in the context of alcohol-induced cortical teratogenesis. (C) 2017 Elsevier Inc. All rights reserved.
机译：虽然脑欠发电是胎儿酒精谱紊乱（FASD）的标志，但引导宽皮质神经发作赤字的机制尚不清楚。已知DNA甲基化通过基因调节调节早期发育和组织规范。在此，我们在FASD的小鼠模型中检查了醇诱导的皮质稀释的DNA甲基化。将C57BL / 6（B6）小鼠从胚胎（e）天7-16中施用4％醇（v / v）液体饮食，并在E17中收获它们的胚胎，以及异马洛液饮食和实验室种子控制。使用免疫组织化学，Western印迹和甲基-DNA测定评估皮质神经肿瘤，神经表型和甲基化的表观遗传标记。我们认为皮质厚度，神经上皮增殖和神经元迁移和成熟度被发现在E17上被醇浸出。同时，DNA甲基化，包括5-甲基胞嘧啶（5MC）和5-羟基甲基氨基甲基（5HMC），其作为指导正常胚胎皮质发育的内在程序的进展，受到子宫醇暴露的严重影响。细节和说明了皮质细化与该DNA甲基化计划中断的复杂关系。 DNA甲基化，在晚期胚胎阶段的多种皮质层穿过多种皮质层，受到胎儿酒精暴露的高度破坏;这种破坏发生在具有特征发育异常的串联中，从结构到分子范围。最后，我们的调查结果指出了未来探索的重要问题：表观遗传学是否导致神经发育或发展状况是否在酒精诱导的皮质畸胎发生中决定表观遗传学动态。 （c）2017年Elsevier Inc.保留所有权利。

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