The DNA methylation landscape of human early embryos

摘要

DNA methylation is a crucial element in the epigenetic regulation of mammalian embryonic development. However, its dynamic patterns have not been analysed at the genome scale in human pre- implantation embryos due to technical difficulties and the scarcity of required materials. Here we systematically profile the methylome of human early embryos from the zygotic stage through to post- implantation by reduced representation bisulphite sequencing and whole-genome bisulphite sequencing. We show that the major wave of genome-wide demethylation is complete at the 2-cell stage, contrary to previous observations in mice. Moreover, the demethyliation of the paternal genome is much faster than that of the maternal genome, and by the end of the zygotic stage the genome-wide methylation level in male pronuclei is already lower than that in female pronuclei. The inverse correlation between promoter methylation and gene expression gradually strengthens during early embryonic development, reaching its peak at the post-implantation stage. Furthermore, we show that active genes, with the trimethylation of histone H3 at lysine 4 (H3K4me3) mark at the promoter regions in pluripotent human embryonic stem cells, are essentially devoid of DNA methylation in both mature gametes and throughout pre-implantation development. Finally, we also show that long interspersed nuclear elements or short interspersed nuclear elements that are evolutionarily young are dem- ethylated to a milder extent compared to older elements in the same family and have higher abundance of transcripts, indicating that early embryos tend to retain higher residual methylation at the evolutionarily younger and more active transposable elements. Our work provides insists into the critical features of the methylome of human early embryos, as well as its functional relation to the regulation of gene expression and the repression of transposable elements.%DNA甲基化的普遍模式在原始生殖细胞中和哺乳动物早期胚胎发育过程中被大举重新编程。这种重新编程在小鼠胚胎中已被很好表征,但我们对人类胚胎中的DNA甲基化动态还缺乏详细的认识。本期Nafure上发表的两篇论文显示,在受精之后,人类基因组的绝大部分都会立即发生DNA甲基化的大量丧失,从而证实这种表观遗传重新编程在演化上是一个保守的发育特征。Hongshan Guo等人生成了碱基分辨率的、胚胎形成过程几个发育阶段的人类配子DNA甲基化图。Zachary Smith等人获得了人类胚胎形成过程几个发育阶段以及在人类胚胎干细胞系衍生过程中的类似的DNA甲基化图。 这两项研究让我们对小鼠与人类甲基化动态之间的差别以及DNA甲基化与基因表达和转座元素之间的功能关系有所认识。