The temporal order of DNA replication [replication timing (RT)] is correlated with chromatin modifications and three-dimensional genome architecture; however, causal links have not been established, largely because of an inability to manipulate the global RT program. We show that loss of RIF1 causes near-complete elimination of the RT program by increasing heterogeneity between individual cells. RT changes are coupled with widespread alterations in chromatin modifications and genome compartmentalization. Conditional depletion of RIF1 causes replication-dependent disruption of histone modifications and alterations in genome architecture. These effects were magnified with successive cycles of altered RT. These results support models in which the timing of chromatin replication and thus assembly plays a key role in maintaining the global epigenetic state.

DNA 复制的时间顺序 [复制计时 (RT)] 与染色质修饰和三维基因组结构相关；然而，因果关系尚未确定，主要是因为无法操纵全球 RT 计划。我们发现，RIF1 的缺失会增加个体细胞之间的异质性，从而导致 RT 程序几乎完全消除。 RT 变化与染色质修饰和基因组区室化的广泛改变相结合。 RIF1 的条件性缺失会导致组蛋白修饰的复制依赖性破坏和基因组结构的改变。这些效应随着连续改变 RT 的周期而放大。这些结果支持这样的模型：染色质复制和组装的时间在维持整体表观遗传状态中起着关键作用。