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    Home > Biochemistry News > Biotechnology News > Nat Genet: Delaying DNA replication fork speeds leads to cell fate changes and enhances cell reprogramming efficiency

    Nat Genet: Delaying DNA replication fork speeds leads to cell fate changes and enhances cell reprogramming efficiency

    • Last Update: 2022-05-23
    • Source: Internet
    • Author: User
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    March 8, 2022 /Bio Valley BIOON/---Cell plasticity is a basic requirement of multicellular organisms
    .
    Cells in early mammalian embryos are most plastic because they can generate every cell type in the body

    .
    In particular, mouse zygotes as well as each blastomere in 2-cell stage embryos are totipotent because they can produce a new organism by themselves

    .
    This is in stark contrast to pluripotent cells, which give rise to all cells in the body, but not extraembryonic tissue

    .
    Therefore, totipotent cells have greater cellular plasticity

    .
    However, the mechanisms that maintain totipotency are not well understood

    .

    DNA replication is a fundamental process of inheritance and epigenetics
    .
    However, how the early mammalian embryo replicates its DNA and whether the acquisition of totipotency is regulated by DNA replication-dependent mechanisms is unknown

    .
    Given that the molecular properties of DNA replication forks are crucial for regulating DNA replication, researchers from research institutions including the University of Munich and the Helmholtz Center Munich set out in a new study to investigate the effects of totipotent cells and cells in vivo.
    Replication fork dynamics in totipotent-like cells in vitro

    .
    The relevant research results were published online in the journal Nature Genetics on March 7, 2022, with the title of "DNA replication fork speed underlies cell fate changes and promotes reprogramming"

    .

    In the new study, the authors used DNA fiber analysis to investigate how pluripotent stem cells can be reprogrammed into totipotent-like 2-cell-like cells (2CLCs)
    .
    They found that totipotent cells in early mouse embryos had a slow DNA replication fork velocity, a feature reproduced by 2CLC, suggesting that DNA replication fork velocity underlies the transition of pluripotent stem cells to a totipotent-like state

    .

    2CLCs co-occur with DNA replication and, compared with pluripotent cells, show changes in replication time (RT), especially early in S phase
    .
    Changes in replication timing occurred prior to the emergence of 2CLC, suggesting that replication timing may lead to changes in gene expression and consequent cell fate reprogramming in pluripotent cells

    .
    Slowing down the DNA replication fork speed can induce the transformation of pluripotent stem cells into 2CLC in experiments

    .

    Decreasing DNA replication fork velocity enhances the developmental potential of embryos after somatic cell nuclear transfer
    .
    Image from Nature Genetics, 2022, doi:10.
    1038/s41588-022-01023-0

    .

    Transplantation of terminally differentiated somatic cells into enucleated oocytes can be reprogrammed to totipotent cells
    .
    However, this process is inefficient and development after the 2-cell stage is often considered a bottleneck

    .
    Given the slower DNA replication fork speed observed in 2-cell stage embryos, these authors explored whether reducing DNA replication fork speed could improve the efficiency of somatic cell nuclear transfer (SCNT) using cumulus cells as donors

    .
    In normally fertilized embryos, hydroxyurea treatment, which results in a decrease in DNA replication fork velocity, did not affect developmental progression

    .
    Notably, hydroxyurea treatment greatly increased the efficiency of SCNTs, resulting in a significantly higher developmental rate compared with the control group (3.
    5-fold, P = 0042)

    .
    RNA-seq analysis of embryos after nuclear transfer showed that cloned embryos efficiently reset their transcriptional profiles

    .
    Thus, these results suggest that manipulation of DNA replication fork speed can improve cloning and facilitate reprogramming to totipotency

    .

    Taken together, these data suggest that DNA replication fork velocity regulates cellular plasticity, and that remodeling of replication signatures leads to changes in cell fate and reprogramming
    .
    (Bioon.
    com)

    References:

    Tsunetoshi Nakatani et al.
    DNA replication fork speed underlies cell fate changes and promotes reprogramming.
    Nature Genetics, 2022, doi:10.
    1038/s41588-022-01023-0.

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