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Embryonic genome instability upon DNA replication timing program emergence


ABSTRACT: Faithful DNA replication is essential for genome integrity. Under-replicated DNA leads to chromosome segregation defects, which are reportedly common during embryogenesis. However, DNA replication regulation remains poorly understood in early mammalian embryos. Here, we constructed a single-cell genome-wide DNA replication atlas of pre-implantation mouse embryos and discovered an abrupt replication program switch accompanied by a transient period of genomic instability. In 1- and 2-cell embryos, we observed the complete absence of a replication timing (RT) program, and the entire genome replicated gradually and uniformly using extremely slow-moving forks. In 4-cell embryos, a somatic-cell-like RT program commenced abruptly. However, the fork speed was still slow, S-phase was extended, and SLX4 DNA repair foci increased during G2/M, which was followed by a transient increase in chromosome segregation errors. Importantly, live imaging captured longer S-phase of error cells, and the breakpoints identified by single-cell genome sequencing were enriched in late-replicating regions. By the 8-cell stage, forks gained speed, S-phase was no longer extended, and chromosome aberrations disappeared. Thus, a transient period of genomic instability exists during normal mouse development, which is preceded by a fragile S-phase lacking the coordination between replisome-level regulation and megabase-scale RT regulation, implicating the importance of their coordination for genome integrity.

ORGANISM(S): Mus musculus

PROVIDER: GSE226309 | GEO | 2024/06/24

REPOSITORIES: GEO

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