The Scientist just came out with a nice article on circular RNAs, including a summary of the latest research and clues to their function. It’s still not clear what circRNAs “do”, but the consensus has been that whatever it is, it doesn’t involve being translated into protein. That no longer appears to be the case:
A little over a year ago, however, Kadener and his colleagues detected something that would upend that assumption: an average-size (37 kilodaltons) protein encoded by a naturally occurring circRNA in Drosophila. Along with collaborators in Germany, Kadener’s group used a method known as ribosomal footprinting to detect RNAs being actively translated in extracts from fly heads. Not only did the researchers discover more than 100 different circRNAs—ranging from around 300 to more than 2,000 nucleotides in length—apparently associating with ribosomes in the cells, they also identified a protein that, based on its sequence, could only have been translated from one of these circles, not from a standard linear transcript. “We could see the protein by Western blot,” Kadener says. “It was being expressed in the synapses of flies.”
There’s also evidence that some of the circRNAs are interacting with miRNAs, which in turn regulate translation.
In 2013, researchers discovered that some circRNAs act as molecular “sponges,” soaking up large quantities of specific microRNAs—tiny, noncoding molecules about 20–25 nucleotides in length. That year, two studies—one by Thomas Hansen of Aarhus University in Denmark and colleagues and one by Rajewsky’s group—simultaneously reported that a circRNA transcribed from the antisense strand of the human CDR1 gene and highly expressed in the brain, called CDR1as by Hansen and ciRS-7 by Rajewsky, has dozens of binding sites for a microRNA known as miR-7.7,8 Hansen’s group also showed that another circRNA, transcribed from the sex-determining region Y (Sry) gene and expressed in mouse testes, could bind microRNA miR-138.
Given the stability of circRNAs, they could be interesting targets for liquid biopsy diagnostics. They’ve already been shown to be present in exosomes and other extracellular vesicles. While they weren’t specifically mentioned in the article, Cofactor Genomics is digging into the potential of using circRNAs for both diagnostics and therapeutics. Something to keep an eye on.
HT @EricTopol
