Santos Fátima, Zakhartchenko Valeri, Stojkovic Miodrag, Peters Antoine, Jenuwein Thomas, Wolf Eckhard, Reik Wolf, Dean Wendy
Laboratory of Developmental Genetics and Imprinting, Developmental Genetics Programme, Babraham Institute, Cambridge CB2 4AT, United Kingdom.
Curr Biol. 2003 Jul 1;13(13):1116-21. doi: 10.1016/s0960-9822(03)00419-6.
During differentiation, somatic nuclei acquire highly specialized DNA and chromatin modifications, which are thought to result in cellular memory of the differentiated state. Upon somatic nuclear transfer into oocytes, the donor nucleus may have to undergo reprogramming of these epigenetic marks in order to achieve totipotency. This may involve changes in epigenetic features similar to those that occur in normal embryos during early development. However, there is accumulating evidence that epigenetic reprogramming is severely deficient in cloned embryos. Several reports reveal inefficient demethylation and inappropriate reestablishment of DNA methylation in quantitative and qualitative patterns on somatic nuclear transfer. Here we examine histone H3 lysine 9 (H3-K9) methylation and acetylation in normal embryos and in those created by somatic nuclear transfer. We find that H3-K9 methylation is reprogrammed in parallel with DNA methylation in normal embryos. However, the majority of cloned embryos exhibit H3-K9 hypermethylation associated with DNA hypermethylation, suggesting a genome-wide failure of reprogramming. Strikingly, the precise epigenotype in cloned embryos depends on the donor cell type, and the proportion of embryos with normal epigenotypes correlates closely with the proportion developing to the blastocyst stage. These results suggest a mechanistic link between DNA and histone methylation in the mammalian embryo and reveal an association between epigenetic marks and developmental potential of cloned embryos.
在分化过程中，体细胞的细胞核会获得高度特化的DNA和染色质修饰，这些修饰被认为会导致细胞对分化状态的记忆。当进行体细胞核移植到卵母细胞中时，供体细胞核可能必须经历这些表观遗传标记的重编程，以实现全能性。这可能涉及类似于正常胚胎早期发育过程中发生的表观遗传特征的变化。然而，越来越多的证据表明，克隆胚胎中的表观遗传重编程严重不足。一些报告显示，在体细胞核移植中，DNA甲基化在定量和定性模式上的去甲基化效率低下以及DNA甲基化的重新建立不当。在这里，我们研究了正常胚胎以及通过体细胞核移植产生的胚胎中的组蛋白H3赖氨酸9（H3-K9）甲基化和乙酰化情况。我们发现，在正常胚胎中，H3-K9甲基化与DNA甲基化并行重编程。然而，大多数克隆胚胎表现出与DNA高甲基化相关的H3-K9高甲基化，这表明在全基因组范围内重编程失败。令人惊讶的是，克隆胚胎中精确的表观基因型取决于供体细胞类型，并且具有正常表观基因型的胚胎比例与发育到囊胚阶段的胚胎比例密切相关。这些结果表明哺乳动物胚胎中DNA和组蛋白甲基化之间存在机制联系，并揭示了表观遗传标记与克隆胚胎发育潜力之间的关联。
