Uncovering the Principles Behind RNA Folding
Do you know RNA folding plays a very crucial role in controlling the gene expression? But how do these folding takes place? Is there any particular predefined format or it occurs randomly? Recently, a Northwestern Engineering research team has uncovered the principles behind RNA folding. The findings showed RNA molecules work as ‘biosensors’ in order to examine and react to various changes in the surroundings by guiding the gene expression. The study is a breakthrough as it can transform the way RNA specific therapeutics was working till now and can even pave the path for new synthetic biology tools to analyze the presence of toxic substances in the environment.
Unfolding the folds
We all know that RNA plays a significant role in storing and transferring genetic information in an organism, while also performing other pivotal functions important to biological systems such as proteins. However, at the centre of its function is the ability to form unique and intricate folding structures that determine the various subsequent activities at the genetic level.
Scientists used next-generation sequencing technology to image the different shapes of the RNA folds. They then analyzed the similarities in the folding patterns and tendencies among the different families of RNA molecules. The findings suggested that certain families of RNA molecules show a similar pattern of folding, and are called riboswitches. Riboswitches are considered to play a role in controlling the gene expression by binding to a molecule, changing its conformation/shape.
“These riboswitches have evolved to fold into very specific shapes so they can recognize other compounds, change their shape when they bind to them, and ultimately induce a change in gene expression,” said Lucks, associate chair and professor of chemical and biological engineering at the McCormick School of Engineering. “There’s been little studied about how exactly they can fold and adjust those shapes, especially since they do so before the RNAs are fully made. We learned that there is an evolutionary pressure on RNAs to not only fold into the final structure, but to have a pathway to do so similarly and efficiently.” – said Lucks, associate chair and professor of chemical and biological engineering at the McCormick School of Engineering.
Understanding the folds
Earlier, the researchers have used high-resolution systems to analyze how a riboswitch recognizes fluoride ion. In one of his earlier published papers (in Nature Chemical Biology), he used the same system to sense ZTP. It is a natural cellular alarmone which is known to function as an “alarm trigger” in the cells.
The findings showed that though there were significant differences among the riboswitches in terms of function, structure and respective target compounds, they followed the same folding pathway. The researchers then used the next-generation sequencing technique to find the similarities in the folding tendencies of these riboswitches.
“Once RNAs are made, they immediately fold into a shape that recognizes the molecule. If the molecule is there, the shape locks in and preserves the structure,” Lucks said. “If the molecule isn’t present, the RNA unravels itself. We found that happened in both instances.
“Whether you’re trying to make an origami crane or frog, the first several steps are pretty much the same,” he added. “While these RNAs look different, they’re amazingly similar when you break them down into their sequence of folding instructions. Finding links to these common features lays the groundwork for coding these principles as design elements for when we want to harness them for our own uses.”
Unfolding the future path
The understanding of the RNA folding mechanism is a breakthrough and it can have significant future applications, from developing potent drug delivery strategies to targeted disease treatments. Though there have been many treatments for diseases caused by misfolded proteins like Alzheimers and Parkinsons, researchers believe that these findings can help treating diseases at RNA level. This may include diseases like spinal muscular atrophy caused due to mis-splicing of the SMN gene.
“You may not only want to target the final structure of an RNA molecule, because they all fold in some sort of structure, but also the folding process to get into that structure,” Lucks said.
The study also encompasses an optimistic step in utilizing the properties of RNA as an effective natural biosensor. Working with Northwestern’s Center for Synthetic Biology and Center for Water Research, Lucks and his lab are pursuing how riboswitches could be used within low-cost synthetic biology platforms to detect toxins in the environment, impacting areas like crop health and water quality.
“As we learn more about the architecture behind how RNAs work, we’ll seek to understand how to make them work better,” Lucks said. “Nature may have evolved to make them do one thing, but we want them to work for us faster or more sensitively. We’re still learning how to do that, but we’re nearing that level of detail where we can truly design around these principles.”