Genome-wide mapping of human DNA replication by optical replication mapping supports a stochastic model of eukaryotic replication.
Genome-wide mapping of human DNA replication by optical replication mapping supports a stochastic model of eukaryotic replication.
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DOI：
10.1016/j.molcel.2021.05.024
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发表时间：
2021-07-15
期刊：
影响因子：
16
通讯作者：
Rhind N
中科院分区：
文献类型：
--
作者：
Wang W;Klein KN;Proesmans K;Yang H;Marchal C;Zhu X;Borrman T;Hastie A;Weng Z;Bechhoefer J;Chen CL;Gilbert DM;Rhind N
真核生物复制动力学的异质性和单个起始位点的低效率使得绘制人类细胞中复制起始的位置和时间变得困难。为了应对这一挑战，我们开发了光学复制映射（ORM），这是一种高通量的单分子方法，并使用它来绘制人类细胞的早期起始事件。我们数据的单分子性质，以及人类基因组在2700万个平均长度约为300 kb的纤维上总共超过2000倍的覆盖范围，使我们能够以高置信度确定起始位点及其发射概率。我们发现，人类复制起始的分布与富集于可接近染色质的异质分布的潜在起始复合物的低效、随机起始一致。这些观察结果与起始时间调节的随机模型一致，并表明复制动力学的随机调节是真核生物复制的基本特征，从酵母到人类都是如此。
The heterogeneous nature of eukaryotic replication kinetics and the low efficiency of individual initiation sites make mapping the location and timing of replication initiation in human cells difficult. To address this challenge, we have developed Optical Replication Mapping (ORM), a high-throughput single-molecule approach, and used it to map early initiation events in human cells. The single-molecule nature of our data, and a total of over 2000-fold coverage of the human genome on 27 million fibers averaging ~300 kb in length, allow us to identify initiation sites and their firing probability with high confidence. We find that the distribution of human replication initiation is consistent with inefficient, stochastic initiation of heterogeneously distributed potential initiation complexes enriched in accessible chromatin. These observations are consistent with stochastic models of initiation-timing regulation and suggest that stochastic regulation of replication kinetics is a fundamental feature of eukaryotic replication, conserved from yeast to humans.
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