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首页> 外文期刊>Frontiers in Genetics >Reduced DNA methylation at the PEG3 DMR and KvDMR1 loci in children exposed to alcohol in utero: a South African Fetal Alcohol Syndrome cohort study
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Reduced DNA methylation at the PEG3 DMR and KvDMR1 loci in children exposed to alcohol in utero: a South African Fetal Alcohol Syndrome cohort study

机译:胎儿胎儿酒精综合症队列研究中,暴露于酒精子宫内的儿童中, PEG3 DMR KvDMR1 位点的DNA甲基化降低

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Fetal alcohol syndrome (FAS) is a devastating developmental disorder resulting from alcohol exposure during fetal development. It is a considerable public health problem worldwide and is characterized by central nervous system abnormalities, dysmorphic facial features, and growth retardation. Imprinted genes are known to play an important role in growth and development and therefore four imprinting control regions (ICRs), H19 ICR , IG-DMR , KvDMR1 and PEG3 DMR were examined. It is proposed that DNA methylation changes may contribute to developmental abnormalities seen in FAS and which persist into adulthood. The participants included FAS children and controls from the Western and Northern Cape Provinces. DNA samples extracted from blood and buccal cells were bisulfite modified, the ICRs were amplified by PCR and pyrosequencing was used to derive a quantitative estimate of methylation at selected CpG dinucleotides: H19 ICR (six CpG sites; 50 controls and 73 cases); KvDMR1 (7, 55, and 86); IG-DMR (10, 56, and 84); and PEG3 DMR (7, 50, and 79). The most profound effects of alcohol exposure are on neuronal development. In this study we report on epigenetic effects observed in blood which may not directly reflect tissue-specific alterations in the developing brain. After adjusting for age and sex (known confounders for DNA methylation), there was a significant difference at KvDMR1 and PEG3 DMR , but not the H19 ICR , with only a small effect (0.84% lower in cases; p = 0.035) at IG-DMR . The two maternally imprinted loci, KvDMR1 and PEG3 DMR , showed lower average locus-wide methylation in the FAS cases (1.49%; p < 0.001 and 7.09%; p < 0.001, respectively). The largest effect was at the PEG3 DMR though the functional impact is uncertain. This study supports the role of epigenetic modulation as a mechanism for the teratogenic effects of alcohol by altering the methylation profiles of imprinted loci in a locus-specific manner.
机译:胎儿酒精综合症(FAS)是一种破坏性的发育障碍,由胎儿发育过程中的酒精暴露引起。它是世界范围内的一个重大公共卫生问题,其特征是中枢神经系统异常,面部畸形和发育迟缓。已知印迹基因在生长和发育中起重要作用,因此检查了四个印迹控制区(ICR),H19 ICR,IG-DMR,KvDMR1和PEG3 DMR。有人提出,DNA甲基化的改变可能会助长FAS中出现的发育异常,并持续到成年期。参与者包括来自西开普省和北开普省的FAS儿童和控制人员。将从血液和颊细胞中提取的DNA样品进行亚硫酸氢盐修饰,通过PCR扩增ICR,并使用焦磷酸测序对选定的CpG二核苷酸H19 ICR(六个CpG位点; 50个对照和73例)进行甲基化的定量估计。 KvDMR1(7、55和86); IG-DMR(10、56和84);和PEG3 DMR(7、50和79)。酒精暴露对神经元发育的最深远影响。在这项研究中,我们报告了在血液中观察到的表观遗传学效应,可能无法直接反映发育中的大脑的组织特异性变化。在调整了年龄和性别(DNA甲基化的已知混杂因素)后,KvDMR1和PEG3 DMR有显着差异,但H19 ICR没有显着差异,而IG-只有很小的影响(在某些情况下,降低了0.84%; p = 0.035)。 DMR。在FAS病例中,两个母系印迹基因座KvDMR1和PEG3 DMR显示出较低的平均基因座全甲基化水平(分别为1.49%; p <0.001和7.09%; p <0.001)。尽管功能影响尚不确定,但对PEG3 DMR影响最大。这项研究通过改变基因座特有的基因座的甲基化谱,支持表观遗传调控作为酒精致畸作用的机制。

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