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From random RNA libraries expressed in yeast, we evolved RNA-based transcriptional activators that are comparable in potency to the strongest natural protein activation domains. The evolved RNAs activated transcription up to 53-fold higher than a three-hybrid positive control using the Gal4 activation domain and only 2-fold lower than the highly active VP16 activation domain. Using a combination of directed evolution and site-directed mutagenesis, we dissected the functional elements of the evolved transcriptional activators. A surprisingly large fraction of RNAs from our library are capable of activating transcription, suggesting that nucleic acids may be well suited for binding transcriptional machinery elements normally recruited by proteins. In addition, our work demonstrates an RNA evolution-based approach to perturbing natural cellular function that may serve as a general tool for studying selectable or …