The researchers 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) transform into specialised cells (e.g., blood, brain, or liver cells).
“Classically, people studying RNA-binding proteins have found that it’s the RNA-binding proteins that do something to RNA to change it during this process, but that’s not really what’s going on here,” said the lead author. “As it turns out, it’s actually the other way around. The hero in this story is the RNA, not the enzymes.”
And while this may sound like a small distinction, this new perspective on riboregulation may represent a more widespread and meaningful principle of biological control.
“This may open up a new chapter of understanding unexpected aspects of controlling metabolism and cell differentiation. There’s every reason to think that this is a ‘tip of the iceberg study’,” said the senior author of this study. “The differentiation of undifferentiated cells and controlling that process is one step away from better understanding cancer.”
The group developed a technology known as RNA interactome capture (RIC) and later an improved version – enhanced RIC (eRIC) – to discover which proteins bind to RNA, including enzymes like ENO1.
“We felt we should take one of these very concrete examples – ENO1 – and actually pursue it deeply to understand what’s behind this RNA binding,” the author explained.
“The coolest new concept is how we now have the transcriptome of the whole cell regulating the enzyme,” the author said. “I think we are just at the start. This is really just an example of unravelling the functional connection between these metabolic enzymes and RNA in mammalian cells. But I think we can build on that.”
The author too points out that this fundamental research provides many new lines of inquiry that his group will continue to pursue, This means answering questions like whether their findings bear out in other enzymes, if they have impacts on other stem cells beyond embryonic stem cells, and whether this protein-RNA interaction is something future drugs might be able to target in the case of cancer cells.
RNA regulates glycolytic enzyme and stem cell differentiation
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