Switch from monoallelic to biallelic human IGF2 promoter methylation during aging and carcinogenesis
Switch from monoallelic to biallelic human IGF2 promoter methylation during aging and carcinogenesis
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DOI：
10.1073/pnas.93.21.11757
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发表时间：
1996-10-15
影响因子：
11.1
通讯作者：
Baylin, SB
中科院分区：
文献类型：
--
作者：
Issa, JPJ;Vertino, PM;Baylin, SB
我们先前已经将人类结肠雌激素受体（ER）基因启动子内的衰老、癌变和从头甲基化联系起来。我们现在研究胰岛素样生长因子II（IGF 2）印迹基因的动态过程。在年轻个体中，IGF 2的P2-4启动子仅在沉默的母体等位基因上甲基化。在衰老过程中，这种启动子甲基化变得更加广泛，并涉及最初未甲基化的等位基因。大多数成人肿瘤，包括结肠癌、乳腺癌、肺癌和白血病，在P2-4 IGF 2启动子处表现出甲基化增加，表明在肿瘤过程中进一步扩散。在肿瘤中，这种甲基化与甲基化的P3启动子的IGF 2表达减少或缺失有关，但维持了P1的表达，P1是一种不包含在IGF 2 CpG岛内的上游启动子。我们的研究结果表明，在衰老和癌变过程中，IGF 2基因印迹启动子的甲基化模式发生了显着的演变，并为异常甲基化和衰老疾病之间的潜在联系提供了进一步的证据。
We have previously linked aging, carcinogenesis, and de novo methylation within the promoter of the estrogen receptor (ER) gene in human colon. We now examine the dynamics of this process for the imprinted gene for insulin-like growth factor II (IGF2). In young individuals, the P2-4 promoters of IGF2 are methylated exclusively on the silenced maternal allele. During aging, this promoter methylation becomes more extensive and involves the originally unmethylated allele. Most adult human tumors, including colon, breast, lung, and leukemias, exhibit increased methylation at the P2-4 IGF2 promoters, suggesting further spreading during the neoplastic process. In tumors, this methylation is associated with diminished or absent IGF2 expression from the methylated P3 promoter but maintained expression from P1, an upstream promoter that is not contained within the IGF2 CpG island. Our results demonstrate a remarkable evolution of methylation patterns in the imprinted promoter of the IGF2 gene during aging and carcinogenesis, and provide further evidence for a potential link between aberrant methylation and diseases of aging.