Principles of MicroRNA–Target Recognition

By J. Brennecke, Alexander Stark, Robert B. Russell, Stephen M Cohen. PLoS Biology, 2005

2,464 citations recorded by the source corpus.

MicroRNAs (miRNAs) are short non-coding RNAs that regulate gene expression in plants and animals. Although their biological importance has become clear, how they recognize and regulate target genes remains less well understood. Here, we systematically evaluate the minimal requirements for functional miRNA–target duplexes in vivo and distinguish classes of target sites with different functional properties. Target sites can be grouped into two broad categories. 5′ dominant sites have sufficient complementarity to the miRNA 5′ end to function with little or no support from pairing to the miRNA 3′ end. Indeed, sites with 3′ pairing below the random noise level are functional given a strong 5′ end. In contrast, 3′ compensatory sites have insufficient 5′ pairing and require strong 3′ pairing for function. We present examples and genome-wide statistical support to show that both classes of sites are used in biologically relevant genes. We provide evidence that an average miRNA has approximately 100 target sites, indicating that miRNAs regulate a large fraction of protein-coding genes and that miRNA 3′ ends are key determinants of target specificity within miRNA families.

Subfields: Cancer Research, Molecular Biology, Plant Science

View Paper: https://www.semanticscholar.org/paper/330e7d895af3abd663452c1d80e25dffcc98d0d0

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Citations in the corpus

IntaRNA: efficient prediction of bacterial sRNA targets incorporating target site accessibility and seed regions (2008, background): “Furthermore, perfect Watson-Crick pairing of seven or eight consecutive bases (typically at positions 2-8) at the 5’ end of animal miRNAs (theseed region) is often sufficient for effective regulation (Brenneckeet al., 2005; Doench and Sharp, 2004; Bentwich, 2005).”
MicroRNA: Biogenesis, Function and Role in Cancer (2010, background): “Target recognition relies heavily on basepairing between the seed (residues 2-8 at the 5’end) of the miRNA guide [156-159].”
The mirtron pathway generates microRNA-class regulatory RNAs in Drosophila. (2007, positive): “Experimental and computational approaches showed that Watson-Crick base pairing between positions 2–8 from the 50 end of an animal miRNA (the miRNA ‘‘seed’’) and a target transcript is typically necessary and often sufficient for direct regulation (Brennecke et al., 2005; Doench and Sharp, 2004; Lai”
MicroRNA expression profiling of human breast cancer identifies new markers of tumor subtype (2007, background): “Because many mRNAs have been under selective pressure to preserve pairing to a six nucleotide sequence in the 5' region of the miRNA known as the miRNA seed (nucleotides 2-7), targets of metazoan miRNAs can be predicted by searching for conserved matches to the seed region [38-42].”
Large-scale sequencing reveals 21U-RNAs and additional microRNAs and endogenous siRNAs in C. elegans. (2006, background): “Most important for target recognition is pairing to the miRNA seed, defined as the 6 nt segment comprising nucleotides 2–7, counting from the 50 terminus of the miRNA (Lewis et al., 2003, 2005; Doench and Sharp, 2004; Brennecke et al., 2005).”
MicroRNA dysregulation in cancer: diagnostics, monitoring and therapeutics. A comprehensive review (2012, neutral): “…the mRNA, recently the target sites have been further divided into three main classes, according to grade and localization of the complementarity (Brennecke et al, 2005): the dominant seed site targets (5 0 seed-only), the 5 0 dominant canonical seed site targets (5 0 dominant) and the 3 0…”
DIANA-microT web server: elucidating microRNA functions through target prediction (2009, neutral): “(10) This field indicates if the interaction may be found in the database of experimentally supported targets (TarBase) or if it has additionally been predicted by another target prediction program (TargetScan or Pictar).”
microRNA Target Predictions across Seven Drosophila Species and Comparison to Mammalian Targets (2005, methodology): “Experimental results have suggested that sites with imperfect nuclei seem to be functional only when compensated by additional binding of the 3 9 end of the microRNA to the target site [14,17].”
MicroRNA-mediated feedback and feedforward loops are recurrent network motifs in mammals. (2007, background): “Since prior experiments have shown that nonconserved sites can confer normal levels of repression when the target transcript is coexpressed with the miRNA (Brennecke et al., 2005; Farh et al., 2005), and that high-affinity sites without perfect seed matches may also be functional in vivo (e.”