STARs are born in Nature Chemical Biology!


James and Melissa’s Nature Chemical Biology paper on “Creating Small Transcription Activating RNAs” (STARs) is out! As we all know, RNA is an awesome molecule that does many things across the cell. It is particularly good at regulating gene expression. However, we noticed recently that of all the things RNA does in nature, one of the things it doesn’t do (to the best of our knowledge) is activate transcription. Since we are always interested in building RNA circuits, but we only had repressors, we thought it was high time we take a look and see if we can make activators.

To make RNA transcriptional activators, James and Melissa tried two different approaches that had a common theme, which was thinking about the decisions that regulatory RNAs make in terms of logic decisions that happen on the RNA structural level. From that perspective, we could then think about inverting the decision making of an RNA transcription repressor to make an activator in terms of inverting the logic of the structural transitions that the RNA undergoes.

It turns out that thinking like this helped us find an extremely simple mechanism for using RNAs to activate transcription that we now call STARs. The STAR system involves placing a special RNA sequence (called a transcriptional terminator) upstream of a target gene that acts as a blockade and prevents the cell from transcribing that gene. When the STAR is present, it removes this blockade, turning on the downstream gene by allowing transcription to take place. We showed that this mechanism is robust, and enables the construction of numerous variants, which we showed were highly orthogonal and even amenable to construction of higher order devices such as RNA-only logic gates. Finally, through characterization of STAR variants, we created design rules that capture the essence of how a STAR’s sequence effects its function, opening up the potential for larger scale de novo design of STAR regulators.

We are extremely excited about STARs for opening up a whole new gene regulatory mechanism with RNA that synthetic biologists can now use. They also work very well – with fold activations approaching 100 in some cases – helping to put RNA regulatory mechanism on strong footing with their protein counterparts!

We are excited to see where STARs go!

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