Human placental-specific epipolymorphism and its association with adverse pregnancy outcomes.
Human placental-specific epipolymorphism and its association with adverse pregnancy outcomes.
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DOI：
10.1371/journal.pone.0007389
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发表时间：
2009-10-19
期刊：
影响因子：
3.7
通讯作者：
Robinson WP
中科院分区：
文献类型：
--
作者：
Yuen RK;Avila L;Peñaherrera MS;von Dadelszen P;Lefebvre L;Kobor MS;Robinson WP
DNA甲基化水平的个体间差异在人类基因组中广泛存在，尽管它在调节基因表达方面起着关键作用。这种变异的性质，包括它的组织特异性性质，以及它在人类表型变异和疾病中可能发挥的作用，仍然缺乏特征。胎盘在调节胎儿生长发育方面发挥着关键作用，对健康具有终生影响。为了确定人类胎盘中具有高度个体间DNA甲基化变异的基因，我们使用Illumina GoldenGate甲基化癌症小组调查了人类基因组，目标是807个基因的1505个CpG位点。虽然许多位点显示出甲基化水平的连续模式，但通过焦磷酸测序证实，Wnt2、TUSC3和EphB4在其启动子区域存在多态的DNA甲基化变异。在检测的100多个胎盘中，有7%-25%的胎盘中存在这些基因的甲基化。这些基因启动子的甲基化状态与mRNA的等位基因表达相一致。在三个提供信息的案例中，观察到TUSC3在母体等位基因上甲基化，因此这可能代表了一个多态印记基因。此外，TUSC3启动子甲基化与子痫前期有关联。这些甲基化等位基因多态(MAP)对人类胎盘多样性的生物学意义进一步被它们在小鼠中的胎盘特异性和缺失所暗示。一项对血液的扩展研究表明，MAP也可能在其他组织中发现，这意味着它们对于组织特异性与复杂疾病的关联具有实用价值。在其他组织中鉴定这种“表型多态”及其在关联性研究中的应用，应该会提高我们对个体间表型变异和复杂疾病易感性的理解。
Interindividual variation in DNA-methylation level is widespread in the human genome, despite its critical role in regulating gene expression. The nature of this variation, including its tissue-specific nature, and the role it may play in human phenotypic variation and disease is still poorly characterized. The placenta plays a critical role in regulating fetal growth and development in ways that have lifelong effects on health. To identify genes with a high degree of interindividual DNA methylation variation in the human placenta, we surveyed the human genome using the Illumina GoldenGate Methylation Cancer panel targeting 1505 CpG sites of 807 genes. While many sites show a continuous pattern of methylation levels, WNT2, TUSC3 and EPHB4 were identified to have a polymorphic “on-or-off” pattern of DNA methylation variation at their promoter region which was confirmed by pyrosequencing. Methylation of these genes can be found in 7%–25% of over 100 placentas tested. The methylation state at the promoter of these genes is concordant with mRNA allelic expression. In three informative cases TUSC3 was observed to be methylated on the maternal allele, and it is thus possible this represents a polymorphically imprinted gene. Furthermore, TUSC3 promoter methylation showed evidence for association with preeclampsia. A biological significance of these methylation allelic polymorphisms (MAPs) to human placental diversity is further implied by their placental specificity and absence in mouse. An extended study of blood suggests that MAPs may also be found in other tissues, implicating their utility for tissue-specific association with complex disorders. The identification of such “epipolymorphism” in other tissues and their use in association studies, should improve our understanding of interindividual phenotypic variability and complex disease susceptibility.
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