Embryonic genome instability upon DNA replication timing program emergence

• 成果类型: Article
• 署名作者: Takahashi, Saori; Kyogoku, Hirohisa; Hayakawa, Takuya; Miura, Hisashi; Oji, Asami; Kondo, Yoshiko; Takebayashi, Shin-ichiro; Kitajima, Tomoya S.; Hiratani, Ichiro
• 署名单位: RIKEN; RIKEN; Kobe University; Mie University
• 刊物名称: Nature
• ISSN/ISSBN: 0028-5235
• DOI: 10.1038/s41586-024-07841-y
• 发表日期: 2024-09-19
• 页码: 686-694
• 关键词: cell-cycle; chromatin architecture; mammalian-cells; mouse embryos; activation; specification; segregation; TRANSITION; profiles; insights

摘要

Faithful DNA replication is essential for genome integrity1-4. Under-replicated DNA leads to defects in chromosome segregation, which are common during embryogenesis5-8. However, the regulation of DNA replication remains poorly understood in early mammalian embryos. Here we constructed a single-cell genome-wide DNA replication atlas of pre-implantation mouse embryos and identified 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 program, and the entire genome replicated gradually and uniformly using extremely slow-moving replication forks. In 4-cell embryos, a somatic-cell-like replication timing program commenced abruptly. However, the fork speed was still slow, S phase was extended, and markers of replication stress, DNA damage and repair increased. This was followed by an increase in break-type chromosome segregation errors specifically during the 4-to-8-cell division with breakpoints enriched in late-replicating regions. These errors were rescued by nucleoside supplementation, which accelerated fork speed and reduced the replication stress. By the 8-cell stage, forks gained speed, S phase was no longer extended and chromosome aberrations decreased. Thus, a transient period of genomic instability exists during normal mouse development, preceded by an S phase lacking coordination between replisome-level regulation and megabase-scale replication timing regulation, implicating a link between their coordination and genome stability. A single-cell genome-wide DNA replication atlas of pre-implantation mouse embryos reveals an abrupt replication program switch accompanied by a transient period of genomic instability.