Familial aggregation of abnormal methylation of parental alleles at the IGF2/H19 and IGF2R differentially methylated regions
Familial aggregation of abnormal methylation of parental alleles at the IGF2/H19 and IGF2R differentially methylated regions
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DOI：
10.1093/hmg/ddg167
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发表时间：
2003-07-01
影响因子：
3.5
通讯作者：
Sapienza, C
中科院分区：
文献类型：
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作者：
Sandovici, I;Leppert, M;Sapienza, C
印迹丧失（LOI）已经在许多类型的人类肿瘤中被观察到，并且可能是某些结肠癌的易感事件。LOI与受影响位点差异甲基化区（DMRs）正常DNA甲基化模式的改变密切相关，但LOI是由随机因素、环境因素还是遗传因素引起的尚不清楚。我们开发了一种基于基因组DNA甲基化敏感限制性内切酶酶切和“热停止”PCR的简单定量测定等位基因甲基化比率的方法。我们在48个三代家庭中检测了IGF2/H19-和igf2r位点的DMRs等位基因甲基化比率。我们观察到IGF2/H19 DMR甲基化比率异常的个体的家族聚类，以及该性状在近20年的稳定性，这与该位点的宪法性LOI主要是由于遗传因素的可能性一致。在IGF2R DMR中，我们观察到等位基因甲基化比率随时间的变化更大，但也观察到异常甲基化比率的家族聚类。总的来说，我们在IGF2R的观察表明，在亲本起源依赖的表观遗传修饰中，共同的遗传因素是造成个体间变异的主要原因。然而，时间变化也发生在孤立的病例中，以及在同一家庭的多个个体中，这表明环境因素也可能起作用。
Loss of imprinting (LOI) has been observed in many types of human tumors and may be a predisposing event in some colon cancers. LOI is strongly associated with alteration of normal DNA methylation patterns in differentially methylated regions (DMRs) of affected loci but it is not known whether LOI is caused by stochastic, environmental or genetic factors. We have developed a simple, quantitative assay for measurement of allelic methylation ratios based on methylation-sensitive restriction endonuclease digestion of genomic DNA and 'hot-stop' PCR. We examined allelic methylation ratios at DMRs within the IGF2/H19- and IGF2R-loci in a panel of 48 three-generation families. We observed familial clustering of individuals with abnormal methylation ratios at the IGF2/H19 DMR, as well as stability of this trait over a period of nearly two decades, consistent with the possibility that constitutional LOI at this locus is due largely to genetic factors. At the IGF2R DMR, we observed more variability in the allelic methylation ratios over time but also observed familial clustering of abnormal methylation ratios. Overall, our observations at IGF2R suggest that shared genetic factors are responsible for a major fraction of inter-individual variability in parental origin-dependent epigenetic modifications. However, temporal changes also occur in isolated cases, as well as within multiple individuals in the same family, indicating that environmental factors may also play a role.