Small RNA and transcriptional upregulation

Abstract

Small RNA molecules, such as microRNA and small interfering RNA, have emerged as master regulators of gene expression through their ability to suppress target genes in a phenomenon collectively called RNA interference (RNAi). There is growing evidence that small RNAs can also serve as activators of gene expression by targeting gene regulatory sequences. This novel mechanism, known as RNA activation (RNAa), appears to be conserved in at least mammalian cells and triggered by both endogenous and artificially designed small RNAs. RNAa depends on Argonaute proteins, but possesses kinetics distinct from that of RNAi. Epigenetic changes are associated with RNAa and may contribute to transcriptional activation of target genes, but the underlying mechanism remains elusive. Given the potential of RNAa as a molecular tool for studying gene function and as a therapeutic for disease, further research is needed to completely elucidate its molecular mechanism in order to refine the rules for target selection and improve strategies for exploiting it therapeutically. WIREs RNA 2011 2 748-760 DOI: 10.1002/wrna.90 For further resources related to this article, please visit the WIREs website.

Figure 1. Whole-genome promoter miRNA target prediction

A. Histogram depicting the number of promoters (1 kb) in the human genome versus the number of sites predicted to be complementary to known human miRNAs. B. The number of miRNA hits in gene promoters positively correlates to the GC content of miRNAs. Shown is a semi-log plot with the number of promoter hits in logarithmic scale on the y-axis and GC content (GC%) of miRNAs in linear scale on the x-axis.

Figure 2. Mechanism for RNAa

An exogenously introduced or naturally occurring saRNA/agRNA is loaded into an Ago protein (e.g. Ago2) where the passenger strand is cleaved and discarded, resulting in an active Ago-RNA complex. This complex gains access to the nuclear compartment by either passive transport when the nuclear envelope disappears during mitosis or active transport mechanisms. The complex may then bind to (A) complementary DNA sequences or (B) nascent cognate transcripts in promoters or 3′ flanking regions and further recruit histone modifiers, leading to an open chromatin structure and active transcription.