小柯机器人

德国慕尼黑大学Maria-Elena Torres-Padilla小组发现，DNA复制叉的速度是细胞命运变化的基础，并促进重编程。该项研究成果于2022年3月7日在线发表在《自然—遗传学》杂志上。

研究人员采用DNA纤维分析来研究了多能干细胞如何被重新编程为全能性的2细胞样细胞（2CLC）。结果表明，早期小鼠胚胎的全能细胞具有缓慢的DNA复制叉速度，2CLC再现了这一特征，这表明复制叉速度是向全能样状态过渡的基础。2CLC与DNA复制同时出现，并显示复制时间（RT）的变化，特别是在早期S期。RT的变化发生在2CLC出现之前，这表明RT可能会导致基因表达的变化和随之而来的细胞命运重塑。放慢复制叉的速度在实验中可以诱导2CLC。在体内，放慢复制叉的速度可以提高体细胞核转移的重编程效率。这些数据表明，复制叉的速度调节细胞的可塑性，以及复制特征的重塑会导致细胞命运和重编程的变化。

据悉，全能性在早期胚胎发育中出现，但其分子基础的特征仍不明显。

附：英文原文

Title: DNA replication fork speed underlies cell fate changes and promotes reprogramming

Author: 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., Arguello Pascualli, Paola Y., Scialdone, Antonio, Yamagata, Kazuo, Whetstine, Johnathan R., Sadreyev, Ruslan I., Torres-Padilla, Maria-Elena

Issue&Volume: 2022-03-07

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.

DOI: 10.1038/s41588-022-01023-0

Source: https://www.nature.com/articles/s41588-022-01023-0

Nature Genetics：《自然—遗传学》，创刊于1992年。隶属于施普林格·自然出版集团，最新IF：41.307
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