Building Transcription Factors from RNA

John-paul Bida

With training in mathematics and computer science from Johns Hopkins University, John-paul Bida entered Mayo Graduate School in 2006 as an unlikely candidate for a thesis project involving yeast and artificial transcription factors. His quantitative thinking and engineering aptitude made the transition fast and fascinating. John-paul’s project involves a bold proposition: RNA molecules can be created to control the transcription of target genes. With the discovery that some natural small RNAs regulate the stability and translation of messenger RNAs, John-paul wondered if a different class of artificial RNAs could be engineered to turn genes off or on at the DNA level by a totally different mechanism. Can RNA molecules be made to direct regulatory proteins to sites near target genes? Powerful yeast genetic selection methods had allowed other laboratories to find unnatural RNA shapes capable of recruiting regulatory proteins. The challenge would be to find a way to create modular domains built from RNA in order to deliver the regulatory domain to specific sites in chromosomes. Such RNAs would need to “figure out” how to bind to molecular landmarks in the neighborhood of the target gene. Because no known principles exist for designing such RNAs, John-paul is using the power of yeast genetic selections. In this way, he is testing millions of random RNA solutions using a yeast growth assay in an attempt to identify any rare RNA sequences that have the necessary homing skill. If such an approach is successful, it might be extended to develop regulatory RNAs that control the expression of disease genes.