Circular RNA that shocked the genetic world
Scientists see the latest thing in a box full of weird RNA: the naturally-occurring circular RNA molecules affect gene expression.
In the latest issue (February 27) of Nature, two important research papers revealed that some circular RNAs act as molecular "sponges" that bind and block tiny gene regulators called microRNAs. In addition, the researchers speculate that circular RNAs also have many other functions. The lead author of one of the Nature articles, Nikolaus Rajewsky, a system biologist at the German Max Delbrück Center for Molecular Medicine, said that these molecules constitute a "cryptic parallel universe of unknown RNAs."
This discovery reminds people again: RNA is not just a trivial messenger between DNA and the encoded protein. In the past 20 years, researchers have discovered a large amount of unconventional RNA. Some are unexpectedly short, some are surprisingly long, while others subvert the conventional function of preventing other RNA strands from translating into proteins. Almost all RNAs are linear, and the few accounts of circular RNAs in plants and animals have also been ignored as genetic accidents or experimental human factors.
In fact, the advantage of linear RNAs may have been an illusion. Classical RNA sequencing methods can only isolate those molecules that have the characteristic molecule "tail". The ends of circular RNAs are linked together and lack these tails, so they are generally ignored.
However, with the advancement of sequencing technology, biologists have accumulated a large number of RNA sequence data sets, some of which come from tailless RNA. Last year, molecular biologist Julia Salzman of Stanford University School of Medicine and colleagues sent the first letter from this ring-shaped universe. They reported that in the search for RNA that might be overlooked by traditional methods, excessive amounts of circular human RNAs were found. When Rajewsky and colleagues tapped a database of circular RNA molecules, they discovered thousands of circular RNAs in C. elegans, mice, and humans.
Sontheimer said: "This is another excellent example of an important RNA flying under the radar."
Another independent research group led by Thomas Hansen and Jorgen Kjems of Aarhus University in Denmark completed the second Nature paper. Both papers focused on a large circular RNA composed of about 1500 nucleotides, which is expressed in the brains of mice and humans. The researchers found that it contains 70 miR-7 binding sites. MicroRNAs are short pieces of RNA that block gene expression by binding and preventing mRNA translation. It has long been known that MiR-7 targets are associated with cancer and Parkinson ’s disease.
The Hansen team found that the expression of this circular RNA blocked miR-7. It inhibits miR-7 activity and increases miR-7 target gene expression. The researchers speculate that this is because this RNA loop captures and inactivates miR-7. Rajewsky's team confirmed that expressing this circular RNA in zebrafish or knocking out miR-7 can alter brain development.
Rajewsky said that circular RNAs may also be sponges of extracellular microRNAs. Some may have binding sites for viral microRNAs, thereby disrupting the immune response. Rajewsky speculates that the circular RNA may even interact with RNA-binding proteins. Salzman agrees: "They are so rich in number and may play multiple functional roles."
So are there other shapes for RNAs? "I don't think we may have missed other forms. But you know someone will always find it," Phillip Sharp, a molecular biologist at Cambridge Massachusetts Institute of Technology, said with a smile.
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