Li E, Beard C, Jaenisch R
Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology, Cambridge 02142.
Nature. 1993 Nov 25;366(6453):362-5. doi: 10.1038/366362a0.
The paternal and maternal genomes are not equivalent and both are required for mammalian development. The difference between the parental genomes is believed to be due to gamete-specific differential modification, a process known as genomic imprinting. The study of transgene methylation has shown that methylation patterns can be inherited in a parent-of-origin-specific manner, suggesting that DNA methylation may play a role in genomic imprinting. The functional significance of DNA methylation in genomic imprinting was strengthened by the recent finding that CpG islands (or sites) in three imprinted genes, H19, insulin-like growth factor 2 (Igf-2), and Igf-2 receptor (Igf-2r), are differentially methylated depending on their parental origin. We have examined the expression of these three imprinted genes in mutant mice that are deficient in DNA methyltransferase activity. We report here that expression of all three genes was affected in mutant embryos: the normally silent paternal allele of the H19 gene was activated, whereas the normally active paternal allele of the Igf-2 gene and the active maternal allele of the Igf-2r gene were repressed. Our results demonstrate that a normal level of DNA methylation is required for controlling differential expression of the paternal and maternal alleles of imprinted genes.
父本和母本基因组并不等同，二者对于哺乳动物的发育都是必需的。亲本基因组之间的差异被认为是由于配子特异性的差异修饰，这一过程被称为基因组印记。对转基因甲基化的研究表明，甲基化模式能够以亲本来源特异性的方式遗传，这表明DNA甲基化可能在基因组印记中发挥作用。最近发现三个印记基因H19、胰岛素样生长因子2（Igf-2）和Igf-2受体（Igf-2r）中的CpG岛（或位点）根据其亲本来源而发生差异甲基化，这一发现强化了DNA甲基化在基因组印记中的功能意义。我们已经检测了这三个印记基因在DNA甲基转移酶活性缺陷的突变小鼠中的表达情况。我们在此报告，所有这三个基因的表达在突变胚胎中均受到影响：H19基因正常沉默的父本等位基因被激活，而Igf-2基因正常活跃的父本等位基因以及Igf-2r基因活跃的母本等位基因则被抑制。我们的结果表明，控制印记基因父本和母本等位基因的差异表达需要正常水平的DNA甲基化。
