DNA replication fork speed underlies cell fate changes and promotes reprogramming

Tsunetoshi Nakatani, Jiangwei Lin, Fei Ji, Andreas Ettinger, Julien Pontabry, Mikiko Tokoro, Luis Altamirano-Pacheco, Jonathan Fiorentino, Elmir Mahammadov, Yu Hatano, Capucine Van Rechem, Damayanti Chakraborty, Elias R. Ruiz-Morales, Paola Y. Arguello Pascualli, Antonio Scialdone, Kazuo Yamagata, Johnathan R. Whetstine, Ruslan I. Sadreyev, Maria Elena Torres-Padilla

Research output: Contribution to journalArticlepeer-review

30 Scopus citations

Abstract

Totipotency emerges in early embryogenesis, but its molecular underpinnings remain poorly characterized. In the present study, we employed DNA fiber analysis to investigate how pluripotent stem cells are reprogrammed into totipotent-like 2-cell-like cells (2CLCs). We show that totipotent cells of the early mouse embryo have slow DNA replication fork speed and that 2CLCs recapitulate this feature, suggesting that fork speed underlies the transition to a totipotent-like state. 2CLCs emerge concomitant with DNA replication and display changes in replication timing (RT), particularly during the early S-phase. RT changes occur prior to 2CLC emergence, suggesting that RT may predispose to gene expression changes and consequent reprogramming of cell fate. Slowing down replication fork speed experimentally induces 2CLCs. In vivo, slowing fork speed improves the reprogramming efficiency of somatic cell nuclear transfer. Our data suggest that fork speed regulates cellular plasticity and that remodeling of replication features leads to changes in cell fate and reprogramming.

Original languageEnglish
Pages (from-to)318-327
Number of pages10
JournalNature Genetics
Volume54
Issue number3
DOIs
StatePublished - Mar 2022

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