Program of Genomics of Differentiation, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892, USA.
Mol Cell Biol. 2010 Mar;30(5):1108-15. doi: 10.1128/MCB.00575-09. Epub 2009 Dec 28.
The 2.4-kb H19 imprinting control region (H19ICR) is required to establish parent-of-origin-specific epigenetic marks and expression patterns at the Igf2/H19 locus. H19ICR activity is regulated by DNA methylation. The ICR is methylated in sperm but not in oocytes, and this paternal chromosome-specific methylation is maintained throughout development. We recently showed that the H19ICR can work as an ICR even when inserted into the normally nonimprinted alpha fetoprotein locus. Paternal but not maternal copies of the ICR become methylated in somatic tissue. However, the ectopic ICR remains unmethylated in sperm. To extend these findings and investigate the mechanisms that lead to methylation of the H19ICR in the male germ line, we characterized novel mouse knock-in lines. Our data confirm that the 2.4-kb element is an autonomously acting ICR whose function is not dependent on germ line methylation. Ectopic ICRs become methylated in the male germ line, but the timing of methylation is influenced by the insertion site and by additional genetic information. Our results support the idea that DNA methylation is not the primary genomic imprint and that the H19ICR insertion is sufficient to transmit parent-of-origin-dependent DNA methylation patterns independent of its methylation status in sperm.
2.4kb 的 H19 印迹控制区 (H19ICR) 是在 Igf2/H19 基因座建立亲本来源特异性表观遗传标记和表达模式所必需的。H19ICR 的活性受 DNA 甲基化调控。ICR 在精子中被甲基化，但在卵母细胞中不被甲基化，这种父本染色体特异性甲基化在整个发育过程中得到维持。我们最近表明，即使插入到通常非印迹的α胎蛋白基因座，H19ICR 也可以作为 ICR 发挥作用。父本而非母本的 ICR 在体细胞组织中被甲基化。然而，异位 ICR 在精子中保持非甲基化。为了扩展这些发现并研究导致 H19ICR 在雄性生殖系中甲基化的机制，我们对新型小鼠敲入系进行了表征。我们的数据证实，2.4kb 元件是一个自主作用的 ICR，其功能不依赖于生殖系甲基化。异位 ICR 在雄性生殖系中被甲基化，但甲基化的时间受到插入位点和其他遗传信息的影响。我们的结果支持这样一种观点，即 DNA 甲基化不是主要的基因组印迹，并且 H19ICR 的插入足以传递亲本来源依赖性的 DNA 甲基化模式，而与精子中的甲基化状态无关。
