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

doi:10.1038/s41588-022-01023-0

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 journal › Article › peer-review

50 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 language	English
Pages (from-to)	318-327
Number of pages	10
Journal	Nature Genetics
Volume	54
Issue number	3
DOIs	https://doi.org/10.1038/s41588-022-01023-0
State	Published - Mar 2022

Keywords

Animals
Cell Differentiation/genetics
Cellular Reprogramming/genetics
DNA Replication/genetics
Embryo, Mammalian
Embryonic Development/genetics
Mice
Pluripotent Stem Cells

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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., Arguello Pascualli, P. Y., Scialdone, A., Yamagata, K., Whetstine, J. R., Sadreyev, R. I., & Torres-Padilla, M. E. (2022). DNA replication fork speed underlies cell fate changes and promotes reprogramming. Nature Genetics, 54(3), 318-327. https://doi.org/10.1038/s41588-022-01023-0

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title = "DNA replication fork speed underlies cell fate changes and promotes reprogramming",

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.",

keywords = "Animals, Cell Differentiation/genetics, Cellular Reprogramming/genetics, DNA Replication/genetics, Embryo, Mammalian, Embryonic Development/genetics, Mice, Pluripotent Stem Cells",

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

note = "{\textcopyright} 2022. The Author(s).",

year = "2022",

month = mar,

doi = "10.1038/s41588-022-01023-0",

language = "English",

volume = "54",

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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, ER, Arguello Pascualli, PY, Scialdone, A, Yamagata, K, Whetstine, JR, Sadreyev, RI & Torres-Padilla, ME 2022, 'DNA replication fork speed underlies cell fate changes and promotes reprogramming', Nature Genetics, vol. 54, no. 3, pp. 318-327. https://doi.org/10.1038/s41588-022-01023-0

TY - JOUR

T1 - DNA replication fork speed underlies cell fate changes and promotes reprogramming

AU - Nakatani, Tsunetoshi

AU - Lin, Jiangwei

AU - Ji, Fei

AU - Ettinger, Andreas

AU - Pontabry, Julien

AU - Tokoro, Mikiko

AU - Altamirano-Pacheco, Luis

AU - Fiorentino, Jonathan

AU - Mahammadov, Elmir

AU - Hatano, Yu

AU - Van Rechem, Capucine

AU - Chakraborty, Damayanti

AU - Ruiz-Morales, Elias R.

AU - Arguello Pascualli, Paola Y.

AU - Scialdone, Antonio

AU - Yamagata, Kazuo

AU - Whetstine, Johnathan R.

AU - Sadreyev, Ruslan I.

AU - Torres-Padilla, Maria Elena

PY - 2022/3

Y1 - 2022/3

N2 - 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.

AB - 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.

KW - Animals

KW - Cell Differentiation/genetics

KW - Cellular Reprogramming/genetics

KW - DNA Replication/genetics

KW - Embryo, Mammalian

KW - Embryonic Development/genetics

KW - Mice

KW - Pluripotent Stem Cells

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U2 - 10.1038/s41588-022-01023-0

DO - 10.1038/s41588-022-01023-0

M3 - Article

C2 - 35256805

SN - 1061-4036

VL - 54

SP - 318

EP - 327

JO - Nature Genetics

JF - Nature Genetics

IS - 3

ER -

DNA replication fork speed underlies cell fate changes and promotes reprogramming

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