Department of Animal Sciences, Purdue University West Lafayette, IN, USA.
Department of Animal Sciences, Purdue University West Lafayette, IN, USA ; Department of Medicine, Indiana University School of Medicine Indianapolis, IN, USA.
Front Genet. 2014 Jun 11;5:173. doi: 10.3389/fgene.2014.00173. eCollection 2014.
Maternal alcohol consumption inflicts a multitude of phenotypic consequences that range from undetectable changes to severe dysmorphology. Using tightly controlled murine studies that deliver precise amounts of alcohol at discrete developmental stages, our group and other labs demonstrated in prior studies that the C57BL/6 and DBA/2 inbred mouse strains display differential susceptibility to the teratogenic effects of alcohol. Since the phenotypic diversity extends beyond the amount, dosage and timing of alcohol exposure, it is likely that an individual's genetic background contributes to the phenotypic spectrum. To identify the genomic signatures associated with these observed differences in alcohol-induced dysmorphology, we conducted a microarray-based transcriptome study that also interrogated the genomic signatures between these two lines based on genetic background and alcohol exposure. This approach is called a gene x environment (GxE) analysis; one example of a GxE interaction would be a gene whose expression level increases in C57BL/6, but decreases in DBA/2 embryos, following alcohol exposure. We identified 35 candidate genes exhibiting GxE interactions. To identify cis-acting factors that mediated these interactions, we interrogated the proximal promoters of these 35 candidates and found 241 single nucleotide variants (SNVs) in 16 promoters. Further investigation indicated that 186 SNVs (15 promoters) are predicted to alter transcription factor binding. In addition, 62 SNVs created, removed or altered the placement of a CpG dinucleotide in 13 of the proximal promoters, 53 of which overlapped putative transcription factor binding sites. These 53 SNVs are also our top candidates for future studies aimed at examining the effects of alcohol on epigenetic gene regulation.
母体酒精摄入会造成多种表型后果，从无法检测到的变化到严重的畸形。我们小组和其他实验室使用严格控制的在特定发育阶段给予精确剂量酒精的鼠类研究，先前的研究表明，C57BL/6 和 DBA/2 近交系小鼠对酒精的致畸作用具有不同的易感性。由于表型多样性不仅取决于酒精暴露的量、剂量和时间，还可能与个体的遗传背景有关。为了确定与酒精诱导的畸形表型差异相关的基因组特征，我们进行了基于微阵列的转录组研究，还根据遗传背景和酒精暴露情况，研究了这两个品系之间的基因组特征。这种方法称为基因 x 环境（GxE）分析；GxE 相互作用的一个例子是，一个基因在 C57BL/6 中的表达水平在酒精暴露后增加，但在 DBA/2 胚胎中降低。我们确定了 35 个表现出 GxE 相互作用的候选基因。为了确定介导这些相互作用的顺式作用因子，我们研究了这 35 个候选基因的近端启动子，在 16 个启动子中发现了 241 个单核苷酸变异（SNV）。进一步的研究表明，186 个 SNV（15 个启动子）预计会改变转录因子结合。此外，在 13 个近端启动子中，有 62 个 SNV 创造、去除或改变了一个 CpG 二核苷酸的位置，其中 53 个位于推测的转录因子结合位点。这 53 个 SNV 也是我们未来研究的首选候选者，旨在研究酒精对表观遗传基因调控的影响。
