Virus Guides Embryo Development After Infecting Primitive Organisms Millions of Years Ago
Ancient viral remnants buried in the genome contribute to a “smooth transition” in embryonic development.
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Ancient viral fragments are far from “junk”
Millions of years ago, ancient retroviruses infected some of the world’s earliest organisms.
While most viruses infect their host, replicate their DNA and leave, retroviruses stick around. They reverse transcribe their RNA genome into DNA, and under certain conditions, this DNA can integrate into the host’s genome.
“When this integration occurs in germ cells (sperm or egg cells), the viral genetic material can be passed on to subsequent generations,” Dr. Nabil Djouder, senior group leader at the Spanish National Cancer Research Centre (CNIO), described.
Endogenous retroviruses, or ERVs, are remnants of ancient retroviral infections that have permanently integrated into the host organism’s genome. For a long time, ERVs were thrust under the umbrella category of “junk DNA”.
What is “junk” DNA?
This is a term that is often used to describe DNA that does not encode protein or lacks a clear, functional role in an organism.
As genomic tools advanced over recent decades, it became increasingly clear that “junk” DNA is not all junk; it might even be treasure.
Researchers have discovered important functions for viral remnants in the genome, such as gene expression regulation, genome stability, maintenance of chromosome structure and other cellular processes. It’s plausible that these viruses actually laid the foundations for many of the traits that make us human.
In their latest research, Djouder and colleagues at CNIO demonstrated how EVRs play a role in embryonic development, particularly during the essential transition from totipotency to pluripotency. The study is published in Science Advances.
The journey from totipotent to pluripotent
Embryonic development is a complex process that involves many stages of cell division and differentiation.
“Our paper describes research on the role of EVRs in the development of mouse embryos, specifically in the transition from totipotency to pluripotency, which occurs shortly after fertilization,” Djouder said. “In the context of embryonic development, totipotent cells can give rise to all the cells needed to form a complete organism, including embryonic cells and extraembryonic cells.”
Pluripotency is a more specialized stage than totipotency, Djouder explained: “Pluripotent cells have the ability to differentiate into any cell type in the organism but cannot form extraembryonic tissues such as the placenta.” Such cells are pivotal for the early stages of embryonic development because they eventually give rise to the various cell layers, tissues and organs of an organism.
Djouder’s group has spent a lot of time studying a complex called the unconventional prefoldin RPB5 interactor, or URI, encoded by the URI gene. Its function is largely unknown, but in worm and fruit fly studies, deletion of URI results in the death of embryos.
In this study, the researchers utilized a suite of techniques to explore why, including genetically engineered mouse models, molecular biochemistry techniques and bioinformatics studies.
“Bioinformatics not only complements our experimental work by handling vast datasets but also allows us to extract meaningful insights from complex biological information. Its growing influence in our research enhances our ability to analyze, interpret and derive valuable conclusions from the wealth of molecular data we generate. The synergy of these diverse approaches ensures a comprehensive and nuanced understanding of the biological processes under investigation,” Djouder said.
Ancient retrovirus helps to modulate gene that is critical for pluripotency
One role of URI is to enable other molecules that are required for pluripotency to “kick into action”. Without URI, this doesn’t happen – and that’s where retroviruses come into play.
Djouder and colleagues found that an endogenous retrovirus protein, known as MERVL-gag, helps to modulate URI. “During the totipotency phase, when there are only two cells in the oocyte, the expression of the viral protein MERVL-gag is high. High expression of the viral protein corresponds to fewer pluripotency factors,” Djouder explained. MERVL-gag binds to URI and prevents it from acting. When the expression of MERVL decreases, pluripotency emerges.
“URI binds and shields pluripotency factors OCT4 and SOX2 from proteasome degradation, while the endogenous retrovirus protein MERVL displaces URI from pluripotent factor interaction, causing their degradation,” Djouder said. “High expression of the viral protein corresponds to a lower presence of pluripotency factors, as it interacts with URI, and pluripotency factors are no longer protected from degradation.”
As these pluripotency factors degrade, totipotency is favored. “When the expression of MERVL decreases, URI is released from the interaction with MERVL and can interact with pluripotency factors to protect them from degradation,” Djouder added.
The research presents a completely novel role for EVRs and reveals a new mechanism by which they directly control the transition from totipotency to pluripotency.
Endogenous retroviruses support a “smooth” progression of early embryonic development
“Our findings reveal the symbiotic coevolution of EVRs with their host cells, ensuring a smooth and timely progression of early embryonic development. This coevolution allows sufficient time for the embryo to adapt and coordinate the seamless transition from totipotency to pluripotency and the specification of cell lineage during embryonic development,” Djouder said.
The study was conducted in mice, which means its findings are not yet applicable to humans, Djouder emphasized. But if the mechanism discovered in this study also exists in humans, what implications could it have? “Since totipotency refers to the ability of a cell to develop into any cell type, as well as into all tissues and organs of the complete organism, URI inhibitors could induce this state, opening new avenues of research in the field of developmental biology and regenerative medicine, including the creation of artificial embryos,” Djouder said.
“Therefore, the significance of human relevance becomes apparent, emphasizing the importance of developing URI inhibitors for further investigation in these fields,” he concluded.
Dr. Nabil Djouder was speaking to Molly Campbell, Senior Science Writer for Technology Networks.
About the interviewee:
Dr. Nabil Djouder, born in France, obtained his PhD in molecular pharmacology from the University of Strasbourg (France) and the University of Freiburg (Germany). In January 2018, Djouder was exceptionally promoted to senior group leader at the CNIO, since then devoting his efforts to understanding the molecular mechanisms linking environmental stresses to disease pathogenesis affecting the organs of the digestive system.
Reference: de la Rosa S, del Mar Rigual M, Vargiu P, Ortega S, Djouder N. Endogenous retroviruses shape pluripotency specification in mouse embryos. Sci Adv. 2024. doi: 10.1126/sciadv.adk9394