Abstract
Small interfering RNAs (siRNAs) and microRNAs (miRNAs) regulate gene expression in a sequence-specific manner. Genes with partial complementarity to siRNA/miRNA sequences in their 3′-untranslated regions (UTRs) are suppressed by a mechanism referred to as the siRNA off-target effect or miRNA-mediated RNA silencing. However, the determinants of such RNA silencing efficiency are poorly understood. Previously, I and co-workers reported that the efficiency of RNA silencing is strongly correlated with the thermodynamic stability of base pairing in the duplex formed within an siRNA/miRNA and between the seed region and its target mRNA. In this review, I first summarize our previous studies that identified the thermodynamic parameter to estimate the silencing efficiency using the calculated base pairing stability: siRNAs downregulate the expression of off-target genes depending on the stability of binding between the siRNA seed region (nucleotides 2–8) and off-target mRNAs, and miRNAs downregulate target mRNA expression depending on the stability of the duplex formed between the 5′ terminus of the miRNA and its target mRNA. I further discuss the possibility that such thermodynamic features of silencing efficiency may have arisen during evolution with increasing body temperature in various organisms.
Highlights
MicroRNAs are a large family of small non-coding RNAs that repress gene expression by inhibiting translation and promoting mRNA decay
More than 2000 miRNAs have been identified in human cells; they are predicted to regulate the activity of hundreds of protein-coding genes to control various aspects of biological processes, including development, differentiation, proliferation, antiviral defense, and metabolism
To understand the regulation of gene expression mediated by miRNA silencing, it is essential to predict the silencing efficiency of each miRNA accurately in addition to its target genes
Summary
MicroRNAs (miRNAs) are a large family of small non-coding RNAs (ncRNAs) that repress gene expression by inhibiting translation and promoting mRNA decay. MiRNA-mediated silencing efficiency is dependent on the seed region and the off-target transcript. The siRNA siRNA guide strand recognizes many mRNA 3’-UTRs with only partial complementarity to the seed guide strand recognizes many mRNA 3’-UTRs with only partial complementarity to the seed region region and downregulates their expression. This effect is referred to as an off-target effect (Figure 1). MiRNA-mediated silencing and siRNA-based off-target effects are thought to share[2,3,23]. SimilarThus, silencing machinery through target recognition processes silencing by miRNA miRNA-mediated silencingcommon and siRNA-based off-target effects are using thetoseed region. The Silencing Efficiency of siRNAs on Off-Target mRNAs Is Regulated by the Stability of Base
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