Ludwig Institute for Cancer Research, La Jolla, CA 92093, USA.
Cell. 2013 May 23;153(5):1134-48. doi: 10.1016/j.cell.2013.04.022. Epub 2013 May 9.
Epigenetic mechanisms have been proposed to play crucial roles in mammalian development, but their precise functions are only partially understood. To investigate epigenetic regulation of embryonic development, we differentiated human embryonic stem cells into mesendoderm, neural progenitor cells, trophoblast-like cells, and mesenchymal stem cells and systematically characterized DNA methylation, chromatin modifications, and the transcriptome in each lineage. We found that promoters that are active in early developmental stages tend to be CG rich and mainly engage H3K27me3 upon silencing in nonexpressing lineages. By contrast, promoters for genes expressed preferentially at later stages are often CG poor and primarily employ DNA methylation upon repression. Interestingly, the early developmental regulatory genes are often located in large genomic domains that are generally devoid of DNA methylation in most lineages, which we termed DNA methylation valleys (DMVs). Our results suggest that distinct epigenetic mechanisms regulate early and late stages of ES cell differentiation.
表观遗传机制被认为在哺乳动物发育中起着至关重要的作用，但它们的确切功能仅部分被理解。为了研究胚胎发育的表观遗传调控，我们将人类胚胎干细胞分化为中胚层、神经祖细胞、滋养层样细胞和间充质干细胞，并系统地表征了每个谱系中的 DNA 甲基化、染色质修饰和转录组。我们发现，在早期发育阶段活跃的启动子往往富含 CG，并且在非表达谱系中沉默时主要涉及 H3K27me3。相比之下，在后期表达偏好的基因的启动子通常 CG 含量较低，并且在抑制时主要采用 DNA 甲基化。有趣的是，早期发育调控基因通常位于大的基因组区域中，在大多数谱系中这些区域通常没有 DNA 甲基化，我们称之为 DNA 甲基化谷（DMVs）。我们的结果表明，不同的表观遗传机制调节着 ES 细胞分化的早期和晚期阶段。
