Cell cycle heterogeneity directs spontaneous 2C state entry and exit in mouse embryonic stem cells

Zhu, Yuqing; Cheng, Chen; Chen, Lang; Zhang, Li; Pan, Hongru; Hou, Linxiao; Sun, Zhen; Zhang, Ling; Fu, Xudong; Chan, Kuan Yoow; Zhang, Jin

doi:10.1016/j.stemcr.2021.09.003

Cited by 15 publications

(17 citation statements)

References 62 publications

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“…However, although chemical inhibition of ATR partly reduced the extent of ZSCAN4 activation, this was not the case in ATR-deficient ESCs 68 . Although checkpoint activation and DNA damage can induce 2CLCs 67 , 2CLC emergence can also occur without checkpoint activation 69 . It is noteworthy that most studies on the role of checkpoint activation in 2CLC induction are based on experimental induction of DNA damage, but only few have been performed in unperturbed conditions.…”

Section: Discussionmentioning

confidence: 99%

DNA replication fork speed underlies cell fate changes and promotes reprogramming

Nakatani

Lin

et al. 2022

Nat Genet

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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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Section: Discussionmentioning

confidence: 99%

DNA replication fork speed underlies cell fate changes and promotes reprogramming

Nakatani

Lin

et al. 2022

Nat Genet

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“…Similar changes in nucleoli were also observed when mESCs were arrested by DNA synthesis inhibitor cytarabine CYT (Zhu et al, 2021a). CYT triggered 2C gene activation independent of the ATR-CHK1 and the p53 pathways (Zhu et al, 2021a).…”

Section: Cell Cycle and Dna Damage Response In Totipotencymentioning

confidence: 69%

“…When rRNA biogenesis was inhibited, the TRIM28/NCL/LIN28 complex dissociated from peri-nucleolar heterochromatin (PNH), which led to Dux loci releasing from PNH and activation of MERVL and 2C genes (Yu et al, 2021). Similar changes in nucleoli were also observed when mESCs were arrested by DNA synthesis inhibitor cytarabine CYT (Zhu et al, 2021a). CYT triggered 2C gene activation independent of the ATR-CHK1 and the p53 pathways (Zhu et al, 2021a).…”

Section: Cell Cycle and Dna Damage Response In Totipotencymentioning

confidence: 91%

The regulation of totipotency transcription: Perspective from in vitro and in vivo totipotency

Liang

2022

Front. Cell Dev. Biol.

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Totipotency represents the highest developmental potency. By definition, totipotent stem cells are capable of giving rise to all embryonic and extraembryonic cell types. In mammalian embryos, totipotency occurs around the zygotic genome activation period, which is around the 2-cell stage in mouse embryo or the 4-to 8-cell stage in human embryo. Currently, with the development of in vitro totipotent-like models and the advances in small-scale genomic methods, an in-depth mechanistic understanding of the totipotency state and regulation was enabled. In this review, we explored and summarized the current views about totipotency from various angles, including genetic and epigenetic aspects. This will hopefully formulate a panoramic view of totipotency from the available research works until now. It can also help delineate the scaffold and formulate new hypotheses on totipotency for future research works.

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“…Notably, the 2C-like transition recapitulates the transcriptomic features of the transition between totipotency and pluripotency of embryonic development[8; 9]. Thus, the 2C-like transition is currently a widely-used model for mechanistic exploration of cell-fate transition between totipotency and pluripotency[2; 3; 4; 7; 8; 9; 10; 11; 12; 13; 14; 15; 16; 17; 18; 19; 20; 21; 22; 23; 24; 25; 26; 27; 28; 29; 30].…”

Section: Introductionmentioning

confidence: 99%

Zfp281 inhibits the pluripotent-to-totipotent state transition in mouse embryonic stem cells

Wen

Lin

et al. 2022

Preprint

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The cell-fate transition between pluripotent and totipotent states determines embryonic development and the first cell-lineage segregation. However, limited by the scarcity of totipotent embryos, regulators on this transition remain largely elusive. A novel model to study the transition has been recently established, named the 2-cell-like (2C-like) model. The 2C-like cells are rare totipotent-like cells in the mouse embryonic stem cell (mESC) culture. Pluripotent mESCs can spontaneously transit into and out of the 2C-like state. We previously dissected the transcriptional roadmap of the transition. In this study, we revealed that Zfp281 is a novel regulator for the pluripotent-to-totipotent transition in mESCs. Zfp281 is a transcriptional factor involved in the cell-fate transition. Our study shows that Zfp281 represses transcripts upregulated during the 2C-like transition via Tet1 and consequentially inhibits mESCs from transiting into the 2C-like state. Interestingly, we found that the inhibitory effect of Zfp281 on the 2C-like transition leads to an impaired 2C-like-transition ability in primed-state mESCs. Altogether, our study reveals a novel mediator for the pluripotent-to-totipotent state transition in mESCs and provides insights into the dynamic transcriptional control of the transition.

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Cell cycle heterogeneity directs spontaneous 2C state entry and exit in mouse embryonic stem cells

Cited by 15 publications

References 62 publications

DNA replication fork speed underlies cell fate changes and promotes reprogramming

DNA replication fork speed underlies cell fate changes and promotes reprogramming

The regulation of totipotency transcription: Perspective from in vitro and in vivo totipotency

Zfp281 inhibits the pluripotent-to-totipotent state transition in mouse embryonic stem cells

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