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Nakatani, T. ; Lin, J. ; Ji, F.* ; Ettinger, A. ; Pontabry, J. ; Tokoro, M.* ; Altamirano-Pacheco, L. ; Fiorentino, J. ; Mahammadov, E. ; Hatano, Y.* ; Van Rechem, C.* ; Chakraborty, D.* ; Ruiz-Morales, E.R. ; Scialdone, A. ; Yamagata, K.* ; Whetstine, J.R.* ; Sadreyev, R.I.* ; Torres-Padilla, M.E.

DNA replication fork speed underlies cell fate changes and promotes reprogramming.

Nat. Genet. 54, 318–327 (2022)
Publ. Version/Full Text Research data DOI
Open Access Gold (Paid Option)
Creative Commons Lizenzvertrag
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.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Embryonic-like Cells; Genome Activation; Nuclear Transfer; Mouse Oocytes; Chromatin; Dynamics; Transcription; Domains; Choice; Genes
ISSN (print) / ISBN 1061-4036
e-ISSN 1546-1718
Journal Nature Genetics
Quellenangaben Volume: 54, Issue: , Pages: 318–327 Article Number: , Supplement: ,
Publisher Nature Publishing Group
Publishing Place New York, NY
Reviewing status Peer reviewed
Grants NIDDK NIH HHS
U.S. Department of Health & Human Services | National Institutes of Health (NIH)
MEXT | Japan Society for the Promotion of Science (JSPS)
Deutsche Forschungsgemeinschaft (German Research Foundation)
Helmholtz Association