Researchers are learning more and more about new reasons for estimating RNA, and the glycolytic enzyme ENO1 seems to have provided another in new research from the European Molecular Biology Laboratory (EMBL) this week, which was published in Molecular cell.
With the support of the MOLIT Institute and the Manfred Lautenschläger Foundation, researchers in the Hentze group at EMBL Heidelberg used mouse embryonic stem cells to discover how messenger RNA molecules bind to and regulate ENO1, an enzyme that breaks down glucose to produce the cellular fuel ATP. This RNA-mediated regulation – riboregulation – can determine how cells grow, and most importantly how undifferentiated cells (specifically embryonic stem cells) are transformed into specialized cells (eg blood, brain or liver cells).
“Classically, people who study RNA-binding proteins have found that it is the RNA-binding proteins that do something with RNA to change it during this process, but that is not really what is going on here,” says Ina Huppertz, formerly postdoc in the Hentze Group and current scientist at the European Research Council. “As it turns out, it’s actually the opposite. The hero of this story is the RNA, not the enzymes.”
And while this may sound like a small difference, this new perspective on riboregulation may represent a more widespread and meaningful principle of biological control.
“This could open up a new chapter to understand unexpected aspects of controlling metabolism and cell differentiation. There is every reason to believe that this is a ‘tip on the iceberg study,'” said Matthias Hentze, EMBL director and leader of this study. The differentiation of undifferentiated cells and controlling that process is a step away from a better understanding of cancer. “
The researchers’ current work actually began at EMBL about 10 years ago. Hentze’s group developed a technology called RNA interactome capture (RIC) and later an improved version – enhanced RIC (eRIC) – to detect which proteins bind to RNA, including enzymes such as ENO1.
“We felt we should take one of these very concrete examples – ENO1 – and actually go deep into understanding what lies behind this RNA binding,” Hentze explained, noting how technologies developed at EMBL combined with underlying methods such as developed elsewhere enabled them to now analyze the role of RNA in this process.
“The coolest new concept is how we now have the transcriptome of the whole cell that regulates the enzyme,” Huppertz said. “I think we’re just getting started. This is really just an example of sorting out the functional link between these metabolic enzymes and RNA in mammalian cells. But I think we can build on that.”
Hentze also points out that this basic research provides many new lines of research that his group will continue to pursue, as well as Huppertz in a research group she will lead in the near future. This means answering questions such as whether their findings show up in other enzymes, whether they have effects on other stem cells beyond embryonic stem cells, and whether this protein-RNA interaction is something future drugs could target in the case of cancer cells. .
And answering these types of scientific questions will require continued intensive collaboration, which Hentze says includes EMBL colleagues and alumni, as well as work with the National Center for Tumors and the University of Heidelberg’s Faculty of Medicine.
By sharing this research, surprises have not only come in the potential change in how researchers think about the role of RNA in cell differentiation, but also the potential scope of this basic research result.
“After giving a talk, I met a scientist who was studying Prochlorococcusa marine cyanobacteria that is the most common photosynthetic organism on earth, “says Hentze.” The researcher had reason to believe that much regulation takes place at RNA level but did not know which proteins in Prochlorococcus binds RNA. So, the technology we have developed to identify RNA-binding proteins in an impartial way has now led to our latest collaboration to help look at RNA regulation in this organism that produces 20% of the world’s oxygen. “
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