Any person begins as a single cell—a fertilized egg—and ends up being an impressive being of some 30 trillion cells, each of them specialized in a task: transporting oxygen in the blood, contracting in the muscle, transmitting thoughts in the brain. . That first cell is totipotent: it has the capacity to generate a complete individual. When it divides, the two resulting cells remain totipotent, but in the next multiplication things change, according to animal studies. 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, in mouse embryos, a surprising actor in this fundamental phase of development: 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 genetic material of viruses, integrated since time immemorial. The investigator Sergio de la Rosa, the first signatory of the study, and his colleagues have observed in mice that one of these past invaders, the endogenous retrovirus MERVL, acts as orchestra director in this necessary transition of cells from totipotency to pluripotency. “Until recently, these viral remains were considered junk DNA, useless or even harmful genetic material,” he explained in a statement. “Intuitively, it was thought that having viruses in the genome could not be good. But in recent years we are realizing that these retroviruses, which have co-evolved with us over millions of years, fulfill important functions, such as regulating other genes,” he noted.
The French pharmacologist Nabil Djouderleader of the CNIO group, has been studying the URI protein, associated with various types of cancer, such as liver and ovary. Previous studies by Djouder have suggested that levels of this protein outside a narrow threshold can either trigger a tumor or prevent it, depending on the context. Balance is essential. His new results show that the activity of the URI protein is key for other molecules to convert the cell into pluripotent. If URI does not act, totipotency remains. Researchers believe that understanding this process in embryo development will help understand similar mechanisms that operate in the appearance of cancer.
The work, published this Wednesday in the magazine Science Advances, reveals that, when the mouse embryo has only two totipotent cells, the ancestral viruses integrated into the DNA take the lead. A protein of viral origin, MERVL-gag, binds to the URI and inactivates it. As embryonic development continues, viral protein levels decline and URIs can intervene, leading to pluripotency. “Our findings reveal the symbiotic coevolution of endogenous retroviruses with their host cells to ensure the smooth and precise progression of early embryonic development,” the authors note in their study. Thanks to the relic of an immemorial virus, the embryo's cells can head to their destination.
Djouder highlighted that it is “a completely new role for endogenous retroviruses.” In his opinion, this new knowledge can be useful in the field of regenerative medicine and the creation of embryo models for scientific research, since it opens a new way to control totipotent cells and produce stable cell lines in the laboratory. .
Enigma in humans
Biologist Marta Shahbazi emphasizes that totipotency in mouse embryos is lost at the four-cell stage, no longer capable of giving rise to a complete individual. “In humans it is not known, 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 that suggests that at the two-cell stage there are already molecular differences between them, but it is not known what this implies in functional terms, in the formation capacity of an organism,” she adds.
Shahbazi highlights that the CNIO team has discovered that, if the URI protein is eliminated, cells are blocked in the earliest phase of development: totipotency. “In order to use these cells in regeneration and creation of embryonic models, the next step would be to demonstrate whether these cells have greater potential, and develop methods so that they could mimic the early phases of development,” he warns.
The biologist Miguel Manzanares applauds the new work, in which he has not participated. “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 maintained. These are mouse-specific,” explains Manzanares, from the Severo Ochoa Molecular Biology Center (CSIC), in Madrid. The researcher emphasizes that the endogenous HERVL retroviruses, equivalent in humans to the mouse MERVL, are also activated in human totipotent cells. And embryonic development in this early phase is similar in rodents and people. “How do you explain that one of the fundamental actors in this process is species-specific? That is a question that is on the table,” she states.
The investigator Francisco José Sánchez Luque highlights 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 a lot of regulatory sequences that have been recycled to do other functions, for example, in the human immune system itself. The retrovirus sequences have been recycled to defend against other retroviruses,” says Sánchez Luque, a biologist who directs the Molecular genetics group of mobile and foreign DNA from 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 has been recycled to regulate a very important process, which is the transition from one cell to two and four cells. It is a very delicate moment, at the beginning of embryonic development, and it turns out that evolution has done it by recycling. It is very possible that something similar happens in humans,” says the biologist.
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