DNA replication in early mammalian embryos is patterned, predisposing lamina-associated regions to fragility

Shuangyi Xu, Ning Wang, Michael V. Zuccaro, Jeannine Gerhardt, Rajan Iyyappan, Giovanna Nascimento Scatolin, Zongliang Jiang, Timour Baslan, Amnon Koren and Dieter Egli ()
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Shuangyi Xu: Columbia University
Ning Wang: Columbia University
Michael V. Zuccaro: Columbia University
Jeannine Gerhardt: Weill Cornell Medical School
Rajan Iyyappan: University of Florida
Giovanna Nascimento Scatolin: University of Florida
Zongliang Jiang: University of Florida
Timour Baslan: The University of Pennsylvania
Amnon Koren: Roswell Park Comprehensive Cancer Center
Dieter Egli: Columbia University

Nature Communications, 2024, vol. 15, issue 1, 1-12

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41467-024-49565-7

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