Each person begins as a single cell – a fertilized egg – and ends up being an impressive creature made up of around 30 trillion cells, each specialized in one task: transporting oxygen in the blood, contracting in the muscle, transmitting thoughts in the brain. . This first cell is totipotent: it has the ability to produce a complete individual. During division, the two resulting cells remain totipotent, but according to animal experiments, everything changes the next time they multiply. These four cells are no longer totipotent but pluripotent: they can give rise to any type of cell in the organism, but not the entire subject. A team from the National Cancer Research Center (CNIO) in Madrid has now discovered a surprising player in this fundamental phase of development in mouse embryos: the relics of viruses from infections that occurred millions of years ago, embedded in the animal DNA.
More than 8% of the human genome corresponds to this virus genome, which has always been integrated. Researcher Sergio de la Rosa, the first signatory of the study, and his colleagues have observed in mice that one of these earlier invaders, the endogenous retrovirus MERVL, acts as a conductor in this necessary transition of cells from totipotency to pluripotency. “Until recently, these viral remnants were considered junk DNA, useless or even harmful genetic material,” he explained in a statement. “Intuitively, people thought that having viruses in the genome couldn’t be good. “But in recent years we are realizing that these retroviruses, which have co-evolved with us over millions of years, perform important functions, such as regulating other genes,” he noted.
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French pharmacologist Nabil Djouder, head of the CNIO group, has been studying the URI protein, which is linked to various cancers such as liver and ovarian cancer, for more than two decades. Previous studies by Djouder have shown that concentrations of this protein outside a narrow threshold can either trigger a tumor or prevent it, depending on the context. Balance is important. Their new results show that the activity of the URI protein is crucial for other molecules to convert the cell into pluripotent cells. If URI does not work, totipotency remains. Researchers believe that understanding this process in embryonic development will help understand the similar mechanisms that occur in the development of cancer.
The work, published this Wednesday in the journal Science Advances, shows that when the mouse embryo has only two totipotent cells, the ancestral viruses integrated into the DNA take over. A protein of viral origin, MERVL-gag, binds to the URI and inactivates it. As embryonic development progresses, viral protein levels decrease and URIs can intervene, leading to pluripotency. “Our results demonstrate the symbiotic coevolution of endogenous retroviruses with their host cells to ensure the smooth and precise progression of early embryonic development,” the authors state in their study. Thanks to the relic of an ancient virus, the embryo's cells can reach their destination.
Djouder emphasized that it is “a completely new role for endogenous retroviruses.” In his opinion, these new findings in the field of regenerative medicine and the creation of embryo models can be useful for scientific research, as they open a new way to control totipotent cells and create stable cell lines in the laboratory.
Mysteries in humans
Biologist Marta Shahbazi emphasizes that totipotency is lost in mouse embryos at the four-cell stage and are no longer able to produce a complete individual. “It is not known in humans because no one has done the experiment,” explains Shahbazi, a Spanish researcher who studies human embryos at the Laboratory of Molecular Biology in Cambridge, United Kingdom. “There is work suggesting that there are molecular differences between them even at the two-cell stage, but it is not known what this means in functional terms, on the educational capacity of an organism,” he adds.
Shahbazi emphasizes that the CNIO team found that eliminating the URI protein blocks cells in the earliest phase of development: totipotency. “To use these cells to regenerate and create embryonic models, the next step would be to show whether these cells have greater potential and to develop methods to mimic the early stages of development,” he warns .
Biologist Miguel Manzanares praises the new work, in which he was not involved. “These endogenous retroviruses are inserted into the genome and no longer move. They are like a fossil footprint. The funny thing is that they are species specific. It is not an event that occurred in a common ancestor of humans and mice, and the mechanism is conserved. These are mouse specific,” explains Manzanares from the Severo Ochoa Molecular Biology Center (CSIC) in Madrid. The researcher emphasizes that endogenous HERVL retroviruses, which in humans correspond to MERVL in mice, are also activated in totipotent cells in humans. And embryonic development in this early phase is similar in rodents and humans. “How do you explain that one of the fundamental players in this process is species specific? “That’s a question that’s on the table,” he says.
Researcher Francisco José Sánchez Luque emphasizes the flexibility of the evolutionary process of living beings. “At first they were infectious, pathogenic viruses, but they became excellent material for evolution to work with. “There are many regulatory sequences that have been recycled to take on other functions, for example in the human immune system itself. Retrovirus sequences have been recycled to defend against other retroviruses,” says Sánchez Luque, a biologist who leads the “Molecular Genetics” group mobile and foreign DNA” at the López Neyra Institute of Parasitology and Biomedicine in Granada. “This study shows that one of the proteins of a retrovirus that was integrated into DNA was recycled to regulate a very important process, namely the transition from one cell to two and four cells.” It's a very delicate one moment at the beginning of embryonic development, and it turns out that evolution did this by recycling. It is entirely possible that something similar happens in humans,” says the biologist.
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