The impact of chromatin modifiers on the timing of locus replication in mouse embryonic stem cells.
The impact of chromatin modifiers on the timing of locus replication in mouse embryonic stem cells.
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DOI：
10.1186/gb-2007-8-8-r169
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发表时间：
2007
期刊：
影响因子：
12.3
通讯作者：
Fisher, Amanda G
中科院分区：
文献类型：
--
作者：
Jorgensen, Helle F;Azuara, Veronique;Amoils, Shannon;Spivakov, Mikhail;Terry, Anna;Nesterova, Tatyana;Cobb, Bradley S;Ramsahoye, Bernard;Merkenschlager, Matthias;Fisher, Amanda G
利用一组缺乏重要染色质修饰物的突变胚胎干细胞系，分析了染色质结构与复制时机之间的关系，揭示了几种染色质修饰物对维持多能ES细胞中卫星序列的正确复制的重要性。S期的基因座复制时间受到严格调控，并与染色质状态相关。胚胎干细胞具有一种不寻常的染色质图谱，其中许多尚未表达的发育调节基因都以组蛋白的活性和抑制性修饰为标志。这种稳定或二价状态的特征也是在ES细胞的早期S期进行位点复制，而在发育选择受限的细胞中复制时间被推迟。在这里，我们使用了一组缺乏重要染色质修饰物的突变小鼠ES细胞系来剖析染色质结构和复制时间之间的关系。我们发现，卫星DNA复制的时间控制对多种染色质修饰物的丢失很敏感，包括MLL、Eed、Dnmt1、SUV39H1/H2和Disher。在染色质修饰突变ES细胞中，包括REx1基因周围的5Mb邻接区在内的多个单拷贝位点的复制时间保持不变，但有一部分基因座受到影响。这一分析证明了染色质修饰物对于维持多能ES细胞中卫星序列的正确复制的重要性，并强调了一些单拷贝基因座对染色质修饰物的影响的敏感性。大量的组蛋白乙酰化与早期复制有很好的相关性。令人惊讶的是，DNA甲基化或组蛋白甲基化的丢失被许多基因座耐受，这表明这些修饰可能对常染色质复制的时间影响较小。
A panel of mutant embryonic stem (ES) cell lines lacking important chromatin modifiers was used to dissect the relationship between chromatin structure and replication timing, revealing the importance of several chromatin modifiers for maintaining correct replication of satellite sequences in pluripotent ES cells. The time of locus replication during S-phase is tightly regulated and correlates with chromatin state. Embryonic stem (ES) cells have an unusual chromatin profile where many developmental regulator genes that are not yet expressed are marked by both active and repressive histone modifications. This poised or bivalent state is also characterized by locus replication in early S-phase in ES cells, while replication timing is delayed in cells with restricted developmental options. Here we used a panel of mutant mouse ES cell lines lacking important chromatin modifiers to dissect the relationship between chromatin structure and replication timing. We show that temporal control of satellite DNA replication is sensitive to loss of a variety of chromatin modifiers, including Mll, Eed, Dnmt1, Suv39h1/h2 and Dicer. The replication times of many single copy loci, including a 5 Mb contiguous region surrounding the Rex1 gene, were retained in chromatin modifier mutant ES cells, although a subset of loci were affected. This analysis demonstrates the importance of chromatin modifiers for maintaining correct replication of satellite sequences in pluripotent ES cells and highlights the sensitivity of some single copy loci to the influence of chromatin modifiers. Abundant histone acetylation is shown to correlate well with early replication. Surprisingly, loss of DNA methylation or histone methylation was tolerated by many loci, suggesting that these modifications may be less influential for the timing of euchromatin replication.