Delayed Accumulation of H3K27me3 on Nascent DNA Is Essential for Recruitment of Transcription Factors at Early Stages of Stem Cell Differentiation.
Delayed Accumulation of H3K27me3 on Nascent DNA Is Essential for Recruitment of Transcription Factors at Early Stages of Stem Cell Differentiation.
复制标题
DOI：
10.1016/j.molcel.2017.03.006
复制
发表时间：
2017-04-20
期刊：
影响因子：
16
通讯作者：
Mazo A
中科院分区：
文献类型：
--
作者：
Petruk S;Cai J;Sussman R;Sun G;Kovermann SK;Mariani SA;Calabretta B;McMahon SB;Brock HW;Iacovitti L;Mazo A
在细胞分化过程中，转录因子（TFs）向常染色质中被抑制基因的募集对于激活新的转录程序至关重要。然而，所有tf的募集，包括先锋因子，都受到含有h3k27me3的浓缩染色质的阻碍。单细胞和基因特异性分析显示，在诱导哺乳动物ESCs分化的最初几个小时内，抑制组蛋白标记H3K27me3的积累在DNA复制后被延迟，这表明在复制基因组的所有区域染色质结构都去致密。这种延迟为谱系特异性tf向DNA的招募提供了一个关键的“机会之窗”。增加复制后H3K27me3的水平，或阻止S期进入，可抑制新tf向DNA的募集，并显著阻断细胞分化。这些发现表明，谱系特异性tf的募集发生在复制后不久，并由去致密的染色质结构促进。这一见解可能解释了干细胞的发育可塑性，并促进了它们用于治疗目的的开发。
Recruitment of transcription factors (TFs) to repressed genes in euchromatin is essential to activate new transcriptional programs during cell differentiation. However, recruitment of all TFs, including pioneer factors, is impeded by condensed H3K27me3-containing chromatin. Single-cell and gene-specific analyses revealed that during the first hours of induction of differentiation of mammalian ESCs, accumulation of the repressive histone mark H3K27me3 is delayed after DNA replication, indicative of decondensed chromatin structure in all regions of the replicating genome. This delay provided a critical ‘window of opportunity’ for recruitment of lineage-specific TFs to DNA. Increasing the levels of post-replicative H3K27me3, or preventing S phase entry inhibited recruitment of new TFs to DNA and significantly blocked cell differentiation. These findings suggest that recruitment of lineage-specifying TFs occurs soon after replication and is facilitated by a decondensed chromatin structure. This insight may explain the developmental plasticity of stem cells and facilitate their exploitation for therapeutic purposes.