Vertebrate genomes replicate according to a precise temporal program strongly correlated with their organization into A/B compartments. Until now, the molecular mechanisms underlying the establishment of early‐replicating domains remain largely unknown. We defined two minimal cis‐element modules containing a strong replication origin and chromatin modifier binding sites capable of shifting a targeted mid‐late‐replicating region for earlier replication. The two origins overlap with a constitutive or a silent tissue‐specific promoter. When inserted side‐by‐side, these modules advance replication timing over a 250 kb region through the cooperation with one endogenous origin located 30 kb away. Moreover, when inserted at two chromosomal sites separated by 30 kb, these two modules come into close physical proximity and form an early‐replicating domain establishing more contacts with active A compartments. The synergy depends on the presence of the active promoter/origin. Our results show that clustering of strong origins located at active promoters can establish early‐replicating domains.

中文翻译：

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与活性启动子相关的强复制子的聚集足以建立早期复制结构域。

脊椎动物基因组根据精确的时间程序进行复制，该程序与其在A / B区室中的组织密切相关。到目前为止，建立早期复制结构域的分子机制仍是未知之数。我们定义了两个最小的顺式包含强大复制起点和染色质修饰剂结合位点的元件模块，能够移动目标中晚期复制区域以实现较早复制。这两个起源与组成型或沉默组织特异性启动子重叠。当并排插入时，这些模块通过与30 kb外的一个内源性源的协作，将复制时间提前到250 kb区域。此外，当这两个模块插入两个相距30 kb的染色体位点时，它们在物理上非常接近，并形成了一个早期复制域，与活性A区室建立了更多接触。协同作用取决于活性启动子/来源的存在。我们的结果表明，位于活跃启动子上的强起源簇可以建立早期复制域。