Totipotency is the ability of a cell to develop into an individual through elaborate processes of embryogenesis and is created during the development of the precursors to sperm and eggs, called germ cells. Understanding the mechanism that provides totipotency is a key goal of regenerative medicine.
Now, a team from Kyoto University’s Institute for Advanced Study of Human Biology (ASHBi) has gained new insights into how totipotency is programmed into germ cells during their development, ready to be triggered for the generation of sperm and ova. Their study is published in The EMBO newspaper.
Group leader Mitinori Saitou of ASHBi says, “A developing embryo requires most cells to give up their totipotency as they specialize and grow in different tissues of a newly formed body. But the primordial germ cells of an embryo are unique. future like sperm and egg, these cells need a mechanism to recover totipotency alongside the other cellular functions that lead to fertilization.”
To better understand this behavior, Saitou’s team followed an in vitro germline differentiation system they created and used a microscope and multi-omics analysis as the cells differentiated into precursors of sperm and eggs. through primordial germ cells. They particularly focused on the three-dimensional behavior of DNA in the cell nucleus.
They revealed that setting up a new life cycle first requires a clean DNA cleanup. All methyl groups, which act as a sort of molecular bookmark for DNA sequences, are removed. The unlabeled copy of DNA is believed to be a key feature of germ cells that gives them totipotency.
DNA strands in germ cells are also uncoiled and primed for activation, creating a so-called highly “euchromatic” state. But at the same time, the nucleus builds additional insulation with a function of key scaffolding molecules to prevent early and abnormal DNA activation.
The team found that during subsequent steps to form sperm precursor cells, some of these changes were gradually reversed. They confirmed that methyl groups were added back to the DNA strands. But, interestingly, the cell continued to develop the “euchromatic” state of DNA in the precursor sperm cells, and the chromosomes also moved to the outer parts of the nucleus, ready for the final cell divisions to form sperm cells. .
Masahiro Nagano, one of the lead authors of the work, said: “The U-bend observed in DNA methylation as euchromatin formation progresses en route to sperm is an interesting finding. Additionally, we We generated the large dataset, setting a new benchmark in this field.These findings will have profound significance for research into hereditary diseases, fertility and future stem cell therapies.
Production of spermatogonial stem cells
Masahiro Nagano et al, nucleome programming is necessary for the foundation of totipotency in mammalian germline development, The EMBO newspaper (2022). DOI: 10.15252/embj.2022110600
Provided by Kyoto University
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