Division of Molecular Genetics, Department of Pediatrics and Naomi Berrie Diabetes Center, Columbia Stem Cell Initiative, Columbia University, New York, NY, 10032, USA.
Graduate Program, Department of Cellular Physiology and Biophysics, Columbia University, New York, NY, USA.
Nat Commun. 2024 Jun 19;15(1):5247. doi: 10.1038/s41467-024-49565-7.
DNA replication in differentiated cells follows a defined program, but when and how it is established during mammalian development is not known. Here we show using single-cell sequencing, that late replicating regions are established in association with the B compartment and the nuclear lamina from the first cell cycle after fertilization on both maternal and paternal genomes. Late replicating regions contain a relative paucity of active origins and few but long genes and low G/C content. In both bovine and mouse embryos, replication timing patterns are established prior to embryonic genome activation. Chromosome breaks, which form spontaneously in bovine embryos at sites concordant with human embryos, preferentially locate to late replicating regions. In mice, late replicating regions show enhanced fragility due to a sparsity of dormant origins that can be activated under conditions of replication stress. This pattern predisposes regions with long neuronal genes to fragility and genetic change prior to separation of soma and germ cell lineages. Our studies show that the segregation of early and late replicating regions is among the first layers of genome organization established after fertilization.
在分化细胞中，DNA 复制遵循一个明确的程序，但在哺乳动物发育过程中，它是何时以及如何建立的尚不清楚。在这里，我们使用单细胞测序表明，在受精后的第一个细胞周期中，母本和父本基因组上的 B 区室和核纤层与晚期复制区域建立了联系。晚期复制区域包含相对较少的活跃起始点和少数但较长的基因以及低 G/C 含量。在牛和小鼠胚胎中，复制时间模式在胚胎基因组激活之前建立。染色体断裂在与人类胚胎一致的部位在牛胚胎中自发形成，优先定位到晚期复制区域。在小鼠中，由于休眠起始点稀疏，晚期复制区域显示出增强的脆弱性，这些休眠起始点可以在复制应激条件下被激活。这种模式使具有长神经元基因的区域在体细胞和生殖细胞系分离之前容易发生脆性和遗传变化。我们的研究表明，早期和晚期复制区域的分离是受精后建立的基因组组织的第一层。
