Nuclear Architecture Organized by Rif1 Underpins the Replication-Timing Program.
Nuclear Architecture Organized by Rif1 Underpins the Replication-Timing Program.
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DOI：
10.1016/j.molcel.2015.12.001
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发表时间：
2016-01-21
期刊：
影响因子：
16
通讯作者：
Buonomo SC
中科院分区：
文献类型：
--
作者：
Foti R;Gnan S;Cornacchia D;Dileep V;Bulut-Karslioglu A;Diehl S;Buness A;Klein FA;Huber W;Johnstone E;Loos R;Bertone P;Gilbert DM;Manke T;Jenuwein T;Buonomo SC
DNA复制在所有的真核生物中都是在时间和空间上有组织的，但是复制定时程序的分子控制和生物学功能还不清楚。Rif1是正常的全基因组复制时间调控所必需的，但其分子功能知之甚少。在这里，我们表明，在小鼠胚胎干细胞中，Rif1涂层后期复制域，并与核纤层蛋白B1，确定大部分的后期复制基因组。Rif1是非核纤层蛋白B1结合晚期结构域复制时间的重要决定因素。我们进一步证明，Rif1定义和限制复制定时域之间的相互作用在G1期，从而揭示了Rif1作为组织者的核架构的功能。Rif1缺失影响复制定时结构域之间相互作用的数量和复制定时特异性。此外，在S期，Rif1确保相互作用域的复制在时间上是协调的。总之，我们的研究确定Rif1作为哺乳动物核结构和复制定时建立之间的分子联系。大多数晚期复制区域由Rif1（RAD）标记。在RAD中晚期复制受到差异调节，其中核纤层蛋白B1稳定结合Rif1限制G1中相同复制时间内的结构域间接触Rif1协调相互作用结构域的复制时间在复制时间建立时，染色质结构域被迫仅与共享相同复制时间的区域相互作用。Foti等人证明Rif1是负责这种约束，因为Rif1缺失导致空间限制的损失，随后是复制定时程序中断。因此，Rif1将核结构和复制定时建立联系起来。
DNA replication is temporally and spatially organized in all eukaryotes, yet the molecular control and biological function of the replication-timing program are unclear. Rif1 is required for normal genome-wide regulation of replication timing, but its molecular function is poorly understood. Here we show that in mouse embryonic stem cells, Rif1 coats late-replicating domains and, with Lamin B1, identifies most of the late-replicating genome. Rif1 is an essential determinant of replication timing of non-Lamin B1-bound late domains. We further demonstrate that Rif1 defines and restricts the interactions between replication-timing domains during the G1 phase, thereby revealing a function of Rif1 as organizer of nuclear architecture. Rif1 loss affects both number and replication-timing specificity of the interactions between replication-timing domains. In addition, during the S phase, Rif1 ensures that replication of interacting domains is temporally coordinated. In summary, our study identifies Rif1 as the molecular link between nuclear architecture and replication-timing establishment in mammals. Most late-replicating regions are marked by Rif1 (RADs) Late replication in RADs is differentially regulated where Lamin B1 is stably bound Rif1 constrains inter-domain contacts within the same replication timing in G1 Rif1 coordinates the replication timing of interacting domains At replication-timing establishment, chromatin domains are forced to interact only with regions sharing the same replication timing. Foti et al. demonstrate that Rif1 is responsible for this constraint because Rif1 deletion leads to loss of spatial limitations followed by replication-timing program disruption. Therefore, Rif1 links nuclear architecture and replication-timing establishment.