Université de Lyon, Lyon, France.
PLoS Comput Biol. 2012;8(4):e1002443. doi: 10.1371/journal.pcbi.1002443. Epub 2012 Apr 5.
In higher eukaryotes, replication program specification in different cell types remains to be fully understood. We show for seven human cell lines that about half of the genome is divided in domains that display a characteristic U-shaped replication timing profile with early initiation zones at borders and late replication at centers. Significant overlap is observed between U-domains of different cell lines and also with germline replication domains exhibiting a N-shaped nucleotide compositional skew. From the demonstration that the average fork polarity is directly reflected by both the compositional skew and the derivative of the replication timing profile, we argue that the fact that this derivative displays a N-shape in U-domains sustains the existence of large-scale gradients of replication fork polarity in somatic and germline cells. Analysis of chromatin interaction (Hi-C) and chromatin marker data reveals that U-domains correspond to high-order chromatin structural units. We discuss possible models for replication origin activation within U/N-domains. The compartmentalization of the genome into replication U/N-domains provides new insights on the organization of the replication program in the human genome.
在高等真核生物中，不同细胞类型的复制程序特异性仍然有待充分理解。我们展示了七个人类细胞系的情况，大约一半的基因组被划分成具有特征性 U 形复制时间分布的域，其边界处的起始较早，而中心处的复制较晚。不同细胞系的 U 域之间存在显著的重叠，并且与表现出 N 形核苷酸组成偏斜的生殖系复制域也存在重叠。从证明平均叉极性直接反映组成偏斜和复制时间分布的导数这一事实出发，我们认为，在 U 域中，该导数呈现 N 形的事实支持了在体细胞和生殖细胞中存在大规模复制叉极性梯度的存在。染色质相互作用（Hi-C）和染色质标记数据的分析表明，U 域对应于高阶染色质结构单元。我们讨论了在 U/N 域内激活复制起点的可能模型。基因组的分区为复制 U/N 域提供了在人类基因组中复制程序组织的新见解。
