Differentially methylated regions of imprinted genes in prenatal, perinatal and postnatal human tissues.
Differentially methylated regions of imprinted genes in prenatal, perinatal and postnatal human tissues.
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DOI：
10.1371/journal.pone.0040924
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Hoyo C
中科院分区：
文献类型：
--
作者：
Murphy SK;Huang Z;Hoyo C
与子宫内暴露相关的表观遗传可塑性可以通过基因表达细微改变的累积效应，从机制上解释观察到的高血压、糖尿病和心血管疾病等常见复杂疾病发生可能性的差异。印迹基因是生长发育的重要介质，其特征是差异甲基化调控区（DMRs）携带亲本等位基因特异性甲基化谱。这个理论上的50%的甲基化水平提供了一个基线，从中可以检测到内源性或外源性诱导的甲基化偏差。我们在大量人类受孕组织、出生时和一岁时收集的匹配颊细胞标本以及脐带血的主要细胞部分中量化了印迹基因DMRs的DNA甲基化，以评估这些区域甲基化的稳定性。在调节IGF2/H19、DLK1/MEG3、MEST、NNAT和SGCE/PEG10印迹结构域的7个DMRs上，使用经过验证的焦磷酸测序法测量DNA甲基化。在所有被分析的受孕组织中，H19、MEST和SGCE/PEG10 DMRs的DMR甲基化没有显著差异（方差分析p < 0.05）。在脑组织（IGF2和MEG3- ig DMR）、肝脏（IGF2和MEG3 DMR）和胎盘（DLK1/MEG3 DMR和NNAT DMR）中观察到几种DMR的甲基化差异。在大多数婴儿中，出生时和一岁时颊细胞的甲基化谱具有可比性，脐带血主要细胞部分的甲基化也具有可比性。一些婴儿在多个DMRs中出现甲基化的时间偏差。个体间和个体内甲基化在某些（但不是全部）DMRs上的相似性支持了这些区域甲基化可以作为有用的暴露生物传感器的可能性。
Epigenetic plasticity in relation to in utero exposures may mechanistically explain observed differences in the likelihood of developing common complex diseases including hypertension, diabetes and cardiovascular disease through the cumulative effects of subtle alterations in gene expression. Imprinted genes are essential mediators of growth and development and are characterized by differentially methylated regulatory regions (DMRs) that carry parental allele-specific methylation profiles. This theoretical 50% level of methylation provides a baseline from which endogenously- or exogenously-induced deviations in methylation can be detected. We quantified DNA methylation at imprinted gene DMRs in a large panel of human conceptal tissues, in matched buccal cell specimens collected at birth and at one year of age, and in the major cell fractions of umbilical cord blood to assess the stability of methylation at these regions. DNA methylation was measured using validated pyrosequencing assays at seven DMRs regulating the IGF2/H19, DLK1/MEG3, MEST, NNAT and SGCE/PEG10 imprinted domains. DMR methylation did not significantly differ for the H19, MEST and SGCE/PEG10 DMRs across all conceptal tissues analyzed (ANOVA p>0.10). Methylation differences at several DMRs were observed in tissues from brain (IGF2 and MEG3-IG DMRs), liver (IGF2 and MEG3 DMRs) and placenta (both DLK1/MEG3 DMRs and NNAT DMR). In most infants, methylation profiles in buccal cells at birth and at one year of age were comparable, as was methylation in the major cell fractions of umbilical cord blood. Several infants showed temporal deviations in methylation at multiple DMRs. Similarity of inter-individual and intra-individual methylation at some, but not all of the DMRs analyzed supports the possibility that methylation of these regions can serve as useful biosensors of exposure.
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