DNA replication fork speed underlies cell fate changes and promotes reprogramming

Nakatani, Tsunetoshi; Lin, Jiangwei; Ji, Fei; Ettinger, Andreas; Pontabry, Julien; Tokoro, Mikiko; Altamirano-Pacheco, Luis; Fiorentino, Jonathan; Mahammadov, Elmir; Hatano, Yu; Rechem, Capucine van; Chakraborty, Damayanti; Ruiz-Morales, Elias R.; Pascualli, Paola Y. Arguello; Scialdone, Antonio; Yamagata, Kazuo; Whetstine, Johnathan R.; Sadreyev, Ruslan I. und Torres-Padilla, Maria-Elena (2022): DNA replication fork speed underlies cell fate changes and promotes reprogramming. In: Nature Genetics, Bd. 54, Nr. 3: S. 318-327

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. Totipotent cells in mouse embryos and 2-cell-like cells have slow DNA replication fork speed. Perturbations that slow replication fork speed promote 2-cell-like cell emergence and improve somatic cell nuclear transfer reprogramming and formation of induced pluripotent stem cell colonies.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Biologie
• Themengebiete: 500 Naturwissenschaften und Mathematik > 570 Biowissenschaften; Biologie
• ISSN: 1061-4036
• Sprache: Englisch
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 213249687