Alcohol exposure alters DNA methylation profiles in mouse embryos at early neurulation.
Alcohol exposure alters DNA methylation profiles in mouse embryos at early neurulation.
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DOI：
10.4161/epi.4.7.9925
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发表时间：
2009-10-01
期刊：
影响因子：
3.7
通讯作者：
Zhou FC
中科院分区：
文献类型：
--
作者：
Liu Y;Balaraman Y;Wang G;Nephew KP;Zhou FC
发育过程中的酒精暴露会导致不同的神经面缺陷和生长迟缓，称为胎儿酒精谱系障碍（FASD）。FASD的潜在机制尚未完全了解。然而，酒精，这是已知的影响甲基供体代谢，可能会诱导异常表观遗传变化，有助于FASD。使用严格控制的全胚胎培养，我们研究了酒精暴露（88 mM）在早期胚胎神经元形成的影响，全基因组DNA甲基化和基因表达的C57 BL/6小鼠。使用MeDIP（甲基化DNA免疫沉淀）结合微阵列（MeDIP芯片）分析小鼠发育早期启动子CpG岛周围的DNA甲基化景观。在神经胚形成早期，与高CpG启动子（HCP）相关的基因甲基化率较低，但表达率较高。观察到酒精诱导的DNA甲基化改变，特别是在染色体7、10和X上的基因中;值得注意的是，与没有神经管缺陷的胚胎相比，在暴露于酒精的具有神经管缺陷表型的胚胎中观察到染色体10和X上甲基化增加的基因数量增加了>10倍。在印迹基因中发现了甲基化的显著变化，这些基因已知在细胞周期、生长、凋亡、癌症中起作用，并且在大量与嗅觉相关的基因中也发现了甲基化的显著变化。改变的甲基化与84个基因表达的显著变化相关（p < 0.01）。Sequenom EpiTYPER DNA甲基化分析用于验证MeDIP-芯片数据。证实了已知在代谢中起作用的基因（Cyp 4f 13）甲基化增加，与发育（Nlgn 3、Elavl 2、Sox 21和Sim 1）、印记（Igf 2 r）和染色质（Hist 1h 3d）相关的基因甲基化减少。在FASD的小鼠模型中，我们首次表明，神经形成早期的酒精暴露可诱导DNA甲基化模式的异常变化，并伴有基因表达的相关变化，这些变化可能共同导致观察到的异常胎儿发育。
Alcohol exposure during development can cause variable neurofacial deficit and growth retardation known as fetal alcohol spectrum disorders (FASD). The mechanism underlying FASD is not fully understood. However, alcohol, which is known to affect methyl donor metabolism, may induce aberrant epigenetic changes contributing to FASD. Using a tightly controlled whole-embryo culture, we investigated the effect of alcohol exposure (88 mM) at early embryonic neurulation on genome-wide DNA methylation and gene expression in the C57BL/6 mouse. The DNA methylation landscape around promoter CpG islands at early mouse development was analyzed using MeDIP (methylated DNA immunoprecipitation) coupled with microarray (MeDIP-chip). At early neurulation, genes associated with high CpG promoters (HCP) had a lower ratio of methylation but a greater ratio of expression. Alcohol-induced alterations in DNA methylation were observed, particularly in genes on chromosomes 7, 10 and X; remarkably, a >10 fold increase in the number of genes with increased methylation on chromosomes 10 and X was observed in alcohol-exposed embryos with a neural tube defect phenotype compared to embryos without a neural tube defect. Significant changes in methylation were seen in imprinted genes, genes known to play roles in cell cycle, growth, apoptosis, cancer, and in a large number of genes associated with olfaction. Altered methylation was associated with significant (p < 0.01) changes in expression for 84 genes. Sequenom EpiTYPER DNA methylation analysis was used for validation of the MeDIP-chip data. Increased methylation of genes known to play a role in metabolism (Cyp4f13) and decreased methylation of genes associated with development (Nlgn3, Elavl2, Sox21 and Sim1), imprinting (Igf2r) and chromatin (Hist1h3d) was confirmed. In a mouse model for FASD, we show for the first time that alcohol exposure during early neurulation can induce aberrant changes in DNA methylation patterns with associated changes in gene expression, which together may contribute to the observed abnormal fetal development.
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