Division of Biostatistics, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.
Epigenetics. 2009 Oct 1;4(7):500-11. doi: 10.4161/epi.4.7.9925.
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 (88mM) 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.
酒精暴露于发育过程中可能导致多种神经面部缺陷和生长迟缓，即胎儿酒精谱系障碍（FASD）。FASD 的发病机制尚不完全清楚。然而，酒精已知会影响甲基供体代谢，可能会导致异常的表观遗传变化，从而导致 FASD。我们使用严格控制的整体胚胎培养技术，研究了早期胚胎神经形成时酒精暴露（88mM）对 C57BL/6 小鼠全基因组 DNA 甲基化和基因表达的影响。使用 MeDIP（甲基化 DNA 免疫沉淀）与微阵列（MeDIP-chip）相结合，分析了早期小鼠发育过程中启动子 CpG 岛周围的 DNA 甲基化图谱。在早期神经形成时，与高 CpG 启动子（HCP）相关的基因具有较低的甲基化比率，但具有更高的表达比率。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；值得注意的是，与没有神经管缺陷的胚胎相比，具有神经管缺陷表型的胚胎中，染色体 10 和 X 上的甲基化增加的基因数量增加了 10 倍以上。在印记基因、已知在细胞周期、生长、凋亡、癌症中发挥作用的基因以及与嗅觉相关的大量基因中观察到显著的甲基化变化。改变的甲基化与 84 个基因的表达显著变化（p<0.01）相关。Sequenom EpiTYPER DNA 甲基化分析用于验证 MeDIP-chip 数据。证实了代谢相关基因（Cyp4f13）的甲基化增加和发育相关基因（Nlgn3、Elavl2、Sox21 和 Sim1）、印记基因（Igf2r）和染色质基因（Hist1h3d）的甲基化减少。在 FASD 的小鼠模型中，我们首次表明，早期神经形成时酒精暴露可引起 DNA 甲基化模式的异常改变，并伴有基因表达的改变，这可能共同导致观察到的胎儿发育异常。
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