Boyer Laurie A, Plath Kathrin, Zeitlinger Julia, Brambrink Tobias, Medeiros Lea A, Lee Tong Ihn, Levine Stuart S, Wernig Marius, Tajonar Adriana, Ray Mridula K, Bell George W, Otte Arie P, Vidal Miguel, Gifford David K, Young Richard A, Jaenisch Rudolf
Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, Massachusetts 02142, USA.
Nature. 2006 May 18;441(7091):349-53. doi: 10.1038/nature04733. Epub 2006 Apr 19.
The mechanisms by which embryonic stem (ES) cells self-renew while maintaining the ability to differentiate into virtually all adult cell types are not well understood. Polycomb group (PcG) proteins are transcriptional repressors that help to maintain cellular identity during metazoan development by epigenetic modification of chromatin structure. PcG proteins have essential roles in early embryonic development and have been implicated in ES cell pluripotency, but few of their target genes are known in mammals. Here we show that PcG proteins directly repress a large cohort of developmental regulators in murine ES cells, the expression of which would otherwise promote differentiation. Using genome-wide location analysis in murine ES cells, we found that the Polycomb repressive complexes PRC1 and PRC2 co-occupied 512 genes, many of which encode transcription factors with important roles in development. All of the co-occupied genes contained modified nucleosomes (trimethylated Lys 27 on histone H3). Consistent with a causal role in gene silencing in ES cells, PcG target genes were de-repressed in cells deficient for the PRC2 component Eed, and were preferentially activated on induction of differentiation. Our results indicate that dynamic repression of developmental pathways by Polycomb complexes may be required for maintaining ES cell pluripotency and plasticity during embryonic development.
胚胎干细胞（ES细胞）在自我更新的同时保持分化为几乎所有成体细胞类型的能力，其机制尚未完全明确。多梳蛋白家族（PcG）是转录抑制因子，通过对染色质结构进行表观遗传修饰，在多细胞动物发育过程中帮助维持细胞特性。PcG蛋白在早期胚胎发育中起重要作用，并与ES细胞的多能性有关，但在哺乳动物中其靶基因却知之甚少。在此我们表明，PcG蛋白直接抑制小鼠ES细胞中大量的发育调节因子，如果这些因子表达，否则将促进分化。通过对小鼠ES细胞进行全基因组定位分析，我们发现多梳抑制复合物PRC1和PRC2共同占据了512个基因，其中许多基因编码在发育中起重要作用的转录因子。所有共同占据的基因都含有修饰的核小体（组蛋白H3上的赖氨酸27三甲基化）。与在ES细胞基因沉默中起因果作用一致，PcG靶基因在PRC2组分Eed缺陷的细胞中去抑制，并在诱导分化时优先被激活。我们的结果表明，在胚胎发育过程中，多梳复合物对发育途径的动态抑制可能是维持ES细胞多能性和可塑性所必需的。
