Promoter-specific modulation of insulin-like growth factor II genomic imprinting by inhibitors of DNA methylation
Promoter-specific modulation of insulin-like growth factor II genomic imprinting by inhibitors of DNA methylation
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DOI：
10.1074/jbc.271.30.18253
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发表时间：
1996-07-26
影响因子：
4.8
通讯作者：
Hoffman, AR
中科院分区：
文献类型：
--
作者：
Hu, JF;Vu, TH;Hoffman, AR
胰岛素样生长因子II （IGF-II）基因在大多数正常组织中只有父本等位基因被转录，然而在一些人类肿瘤中，IGF-II由两个亲本等位基因表达。为了探索IGF-II印迹的潜在机制，我们在培养的人和小鼠星形胶质细胞中检测了DNA去甲基化的影响。当这些细胞用DNA去甲基化剂5-氮胞苷或2-脱氧-5-氮胞苷处理时，观察到IGF-II的表达增加。等位基因分析表明，在DNA去甲基化之后，IGF-II mRNA的增加主要来自正常抑制的母体等位基因。对启动子使用情况的检查显示，只有最近端的启动子（小鼠的mP3和人类的hP4）对DNA去甲基化药物有反应，而来自其他启动子的IGF-II的表达保持不变。这些启动子中IGF-II的表达增强表明在mP3和hP4中或附近存在甲基化反应元件。这项研究表明，DNA去甲基化剂增加IGF-II表达主要是通过激活最近的IGF-II启动子来刺激正常印迹的等位基因。
The insulin-like growth factor II (IGF-II) gene is maternally imprinted in most normal tissues with only the paternal allele being transcribed, In several human tumors, however, IGF-II is expressed from both parental alleles. To explore the underlying mechanism of IGF-II imprinting, we have examined the effect of DNA demethylation in cultured human and mouse astrocyte cells. An increased expression of IGF-II was observed when these cells were treated with the DNA demethylating agents, 5-azacytidine or 2-deoxy-5-azacytidine. Allelic analysis indicated that, following DNA demethylation, the increment in IGF-II mRNA was primarily derived from the normally suppressed maternal allele. Examination of promoter usage revealed that only the most proximal promoter (mP3 in mouse and hP4 in human) responded to DNA demethylating agents, whereas the expression of IGF-II from the other promoters remained unchanged. The enhanced expression of IGF-II from these promoters suggests the presence of a methylation response element in or near mP3 and hP4. This study indicates that DNA demethylating agents increase IGF-II expression primarily by stimulating the normally imprinted allele through the activation of the most proximal IGF-II promoter.