DNA replication fork speed underlies cell fate changes and promotes reprogramming

• Published in: Nature genetics Vol. 54; no. 3; pp. 318 - 4
• Main Authors: Nakatani, Tsunetoshi, Lin, Jiangwei, Ji, Fei, Ettinger, Andreas, Pontabry, Julien, Tokoro, Mikiko, Altamirano-Pacheco, Luis, Fiorentino, Jonathan, Mahammadov, Elmir, Hatano, Yu, Van Rechem, Capucine, Chakraborty, Damayanti, Ruiz-Morales, Elias R, Pascualli, Paola Y Arguello, Scialdone, Antonio, Yamagata, Kazuo, Whetstine, Johnathan R, Sadreyev, Ruslan I, Torres-Padilla, Maria-Elena
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group 01.03.2022
• Subjects: Cell cycle; Cell fate; Deoxyribonucleic acid; DNA; DNA biosynthesis; Embryogenesis; Embryonic growth stage; Embryos; Fabric analysis; Gene expression; Kinases; Nuclear transfer; Plastic foam; Pluripotency; Replication; Somatic cell nuclear transfer; Stem cell transplantation; Stem cells
• DOI: 10.1038/s41588-022-01026-x
• ISSN: 1061-4036

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.