The transcriptional and epigenomic foundations of ground state pluripotency.
The transcriptional and epigenomic foundations of ground state pluripotency.
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DOI：
10.1016/j.cell.2012.03.026
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发表时间：
2012-04-27
期刊：
影响因子：
64.5
通讯作者：
Stunnenberg HG
中科院分区：
文献类型：
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作者：
Marks H;Kalkan T;Menafra R;Denissov S;Jones K;Hofemeister H;Nichols J;Kranz A;Stewart AF;Smith A;Stunnenberg HG
在血清中生长的小鼠胚胎干（ES）细胞比在含有两种激酶（Mek和GSK3）的抑制剂的限定培养基中培养的ES细胞在形态和多能性因子表达方面表现出更大的异质性，这是一种被称为"2i"的条件，其被假定为建立幼稚基态。我们发现，血清和2i生长的ES细胞的转录组和表观基因组图谱是不同的。2i处理的细胞表现出谱系相关基因的表达较低，抑制性组蛋白修饰H3K27me3启动子的流行率降低，以及被认为标志基因准备上调或下调的二价结构域较少。尽管如此，血清和2i培养的ES细胞具有相似的分化潜力。发育基因在2i中的早熟转录受到RNA聚合酶II启动子近端暂停的抑制。这些研究结果表明，转录增强和允许的染色质背景下的基态的特点，从它的退出可能不需要一个亚稳态的中间或多谱系引发。幼稚多能性的高分辨率全基因组转录组和表观基因组-幼稚ES细胞中启动子处的H3K27me3减少和二价结构域减少-幼稚状态中谱系引发减少和RNA聚合酶II暂停增加-幼稚ES细胞未显示分化延迟基态多能性的特征在于允许的染色质背景，但由于启动子近端转录暂停的普遍存在，基因表达并不是混杂的。
Mouse embryonic stem (ES) cells grown in serum exhibit greater heterogeneity in morphology and expression of pluripotency factors than ES cells cultured in defined medium with inhibitors of two kinases (Mek and GSK3), a condition known as “2i” postulated to establish a naive ground state. We show that the transcriptome and epigenome profiles of serum- and 2i-grown ES cells are distinct. 2i-treated cells exhibit lower expression of lineage-affiliated genes, reduced prevalence at promoters of the repressive histone modification H3K27me3, and fewer bivalent domains, which are thought to mark genes poised for either up- or downregulation. Nonetheless, serum- and 2i-grown ES cells have similar differentiation potential. Precocious transcription of developmental genes in 2i is restrained by RNA polymerase II promoter-proximal pausing. These findings suggest that transcriptional potentiation and a permissive chromatin context characterize the ground state and that exit from it may not require a metastable intermediate or multilineage priming. ► High-resolution genome-wide transcriptome and epigenome of naive pluripotency ► Reduced H3K27me3 at promoters and fewer bivalent domains in naive ES cells ► Reduced lineage priming and increased RNA polymerase II pausing in the naive state ► Naive ES cells show no delay in differentiation Ground state pluripotency is characterized by a permissive chromatin context, but gene expression is not promiscuous due to the high prevalence of promoter-proximal pausing of transcription.
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