Polycomb complexes repress developmental regulators in murine embryonic stem cells
Polycomb complexes repress developmental regulators in murine embryonic stem cells
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DOI：
10.1038/nature04733
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发表时间：
2006-05-18
期刊：
影响因子：
64.8
通讯作者：
Jaenisch, R
中科院分区：
文献类型：
--
作者：
Boyer, LA;Plath, K;Jaenisch, R
胚胎干（ES）细胞自我更新同时保持分化为几乎所有成体细胞类型的能力的机制尚不清楚。多梳族 (PcG) 蛋白是转录抑制因子，可通过染色质结构的表观遗传修饰来帮助维持后生动物发育过程中的细胞身份(1)。 PcG 蛋白在早期胚胎发育中具有重要作用(2-6)，并且与 ES 细胞多能性有关(2)，但在哺乳动物中，其靶基因很少为人所知。在这里，我们发现 PcG 蛋白直接抑制小鼠 ES 细胞中的大量发育调节因子，否则这些调节因子的表达会促进分化。通过对小鼠 ES 细胞进行全基因组定位分析，我们发现 Polycomb 抑制复合物 PRC1 和 PRC2 共同占据 512 个基因，其中许多编码在发育中发挥重要作用的转录因子。所有共占基因均含有修饰的核小体（组蛋白 H3 上的三甲基化 Lys 27）。与 ES 细胞中基因沉默的因果作用一致，PcG 靶基因在缺乏 PRC2 成分 Eed 的细胞中被去抑制，并在诱导分化时优先被激活。我们的结果表明，Polycomb 复合物对发育途径的动态抑制可能是维持胚胎发育过程中 ES 细胞的多能性和可塑性所必需的。
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(1). PcG proteins have essential roles in early embryonic development(2-6) and have been implicated in ES cell pluripotency(2), 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.