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September 03, 2013

Successful development of synthetic RNA switch extension technology points to next-generation technology for control of gene expression

A research team at Kyoto University has succeeded in developing an extension technology for RNA switches, which are devices that allow the expression of a target external gene to be flexibly controlled in response to intracellular conditions. Using the new technology, the researchers have created a so-called "RNA inverter," which enables versatile adjustment and inversion of the switch's action within the cell. Among the members of the research team are Kei Endo, a researcher at CiRA, Professor Tan Inoue of the Graduate School of Biostudies, and Associate Professor Hirohide Saito of CiRA who also serves the Hakubi Center for Advanced Research. 

At present, in order to alter cell fate from iPS cell to differentiated cell, genes have to be induced, for instance by adding growth factor, chemical substances, or other external additives at each stage of the culture process. This means that fate control responsive to intracellular conditions is challenging. The research team introduced above is engaged in the development of RNA switches that will make it possible to control cell fate by adjusting the expression of external genes in response to intracellular conditions (Saito H., Nat. commun. 2:160, 2011). In their previous research, an OFF switch to repress gene expression and an ON switch to activate expression have had to be designed and tuned separately, and it has proved difficult to create a switch based on calculating the functions of a module with the target levels of sensitivity and performance. 

In this latest work, the researchers developed a method that allows ready adjustment and inversion of the action of the RNA switch. They have named the resulting device, made of RNA, an "RNA inverter." The newly developed RNA inverter is able to turn the RNA switch from OFF to ON, switching its function flexibly while maintaining its properties intact.

The synthetic mRNA sequence into which this RNA inverter is inserted is rapidly degraded if the target factor is not expressed within the cell. This means that expression of the target gene is switched OFF. Conversely, when the target factor is expressed, the mRNA binds to the target (detection), the mRNA is stabilized depending on the volume of expression (assessment), and the translation of the target external gene is turned on by the inverter (activation).

Because the RNA switch is able to independently control gene expression by sensing the intracellular conditions, it should lend itself to a range of applications. It could for instance lead to a method for inducing differentiated cells from iPS cells in response to intracellular conditions, or a method of inducing cell death based on exclusive detection of cancer cells. The findings of the research were published in the British scientific journal Nature Communications on September 3, 2013. 

<Journal Information>
Title of Paper
"A versatile cis-acting inverter module for synthetic translational switches"

Kei Endo, Karin Hayashi, Tan Inoue, and Hirohide Saito

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