Small activating RNA (saRNA)-mediated gene activation has opened a new avenue for upregulating the expression of target genes by promoting endogenous transcription, a phenomenon known as RNA activation (RNAa). RNAa is distinct from the established RNAi mechanistic framework, although AGO2 is required by both. The precise mechanism of RNAa is currently disputable and has become a bottleneck in the development of this new technology. saRNA may achieve activation of target genes by directly binding to DNA targets in promoter, or interacting with antisense transcripts transcribed from overlapping promoter sequences, or by silencing other genes. In this chapter, we focused on recent development in our understanding of the target-recognition mechanism in RNAa. Conflicting results on saRNA targets are also discussed. Despite that the target mechanism of RNAa is more complex than expected and not completely understood so far, independent lines of evidence have suggested that saRNAs work by an "on-site" mechanism by binding to target genomic DNA in a "seed-region"-dependent manner. Finally, "off-target" effects of saRNA are observed and should be carefully controlled in designing experiments for and interpreting results from RNAa-related studies.
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