NuRD-dependent DNA methylation prevents ES cells from accessing a trophectoderm fate.
NuRD-dependent DNA methylation prevents ES cells from accessing a trophectoderm fate.
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DOI：
10.1242/bio.2012513
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发表时间：
2012-04-15
期刊：
影响因子：
2.4
通讯作者：
Hendrich B
中科院分区：
文献类型：
--
作者：
Latos PA;Helliwell C;Mosaku O;Dudzinska DA;Stubbs B;Berdasco M;Esteller M;Hendrich B
胚胎干细胞（ES）能够产生胚胎的三个胚层，但不能促进滋养层。胚胎和滋养外胚层细胞命运之间的这种屏障的分子性质尚不清楚，但已知涉及DNA甲基化。在这里，我们证明了核小体重塑和脱乙酰化（NuRD）共阻遏物复合物通过维持ES细胞中滋养外胚层决定因子基因的转录沉默来维持胚胎和滋养外胚层细胞命运之间的发育障碍。我们进一步表明，NuRD活性促进其几个靶启动子的DNA甲基化，在那里它与DNA甲基化非冗余地作用，以执行转录沉默。NuRD缺陷型ES细胞不能完全沉默滋养外胚层决定基因Elf5和Eomes的表达，但这本身不足以诱导向滋养外胚层命运的转分化。相反，这使得ES细胞能够响应适当的细胞外信号激活滋养外胚层特异性基因的表达，使它们能够致力于滋养外胚层细胞的命运。我们的研究结果阐明了胚胎和滋养层细胞命运之间发育障碍的分子本质，并建立了NuRD活性在指定从头DNA甲基化位点中的作用。
Embryonic Stem (ES) cells are able to give rise to the three germ layers of the embryo but are prevented from contributing to the trophoblast. The molecular nature of this barrier between embryonic and trophectodermal cell fates is not clear, but is known to involve DNA methylation. Here we demonstrate that the Nucleosome Remodeling and Deacetylation (NuRD) co-repressor complex maintains the developmental barrier between embryonic and trophectodermal cell fates by maintaining transcriptional silencing of trophectoderm determinant genes in ES cells. We further show that NuRD activity facilitates DNA methylation of several of its target promoters, where it acts non-redundantly with DNA methylation to enforce transcriptional silencing. NuRD-deficient ES cells fail to completely silence expression of the trophectoderm determinant genes Elf5 and Eomes, but this alone is not sufficient to induce transdifferentiation towards the trophectoderm fate. Rather this leaves ES cells capable of activating expression of trophectoderm-specific genes in response to appropriate extracellular signals, enabling them to commit to a trophectodermal cell fate. Our findings clarify the molecular nature of the developmental barrier between the embryonic and trophoblast cell fates, and establish a role for NuRD activity in specifying sites for de novo DNA methylation.
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发表时间：
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影响因子：
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