Micro-RNAs: small is plentiful

Abstract

Two small temporally regulated RNAs (stRNAs)* of approximately 22 nucleotides regulate timing of gene expression during development of the nematode C. elegans. This regulation occurs at a posttranscriptional, presumably translational, level and is distinct from RNA interference (RNAi). One of the two stRNAs, let-7, as well as its target gene, lin-41, are highly conserved even in humans, suggesting a wide employment of stRNA-mediated gene regulation. Recent reports indicate that these two stRNAs are indeed likely to represent only the tip of an iceberg with hundreds or more of additional micro-RNAs (miRNAs) existing in metazoans. miRNAs might thus be previously underestimated key participants in the field of gene regulation.

Figure 1.

Mature stRNAs form duplexes with the 3′ UTRs of their target mRNAs. (A) lin-41 is the major target of let-7 and contains two slightly varying elements in its 3′ UTR that are complementary to the let-7 stRNA as well as one element that is complementary to the second stRNA, lin-4. (B) Examples of potential RNA/RNA duplexes between let-7 and lin-41, and lin-4 and lin-14. In the case of lin-41, a consensus sequence for the two slightly varying 3′ UTR elements is shown. The arrow points to a conserved bulged C that is essential for lin-4 function and might constitute a binding site for additional factors. The bulged A in lin-41 is present in only one of the two elements and thus shown in brackets. (C) stRNAs and miRNAs are transcribed as precursors of ∼60–70 nt that can be folded into a stem-loop structure. Processing releases a mature RNA of ∼22 nt (shaded). For lin-4 and let-7, which are shown here, the mature RNA is released from the 5′ arm of the precursor; however, miRNAs have been identified in which the 3′ arm (or even both arms) is stable.

Figure 2.

Putative miRNA life cycle. The model ilustrates important stages in the life cycle of a miRNA, all of which might be regulated. (1) miRNAs are transcribed as precursors by an, as yet, unidentified RNA polymerase (Pol). (2) Following its export to the cytoplasm by a likewise unidentified factor the precursor is processed (3) into the mature miRNA. (However, it should be noted that the site of pre-miRNA processing is currently unknown so that it is also possible that processing occurs in the nucleus and the mature miRNA is the substrate for nuclear export.) Pre-miRNA processing involves Dicer and, presumably, one or more cofactors such as AGL-1/AGL-2. These factors might then also be involved in delivery of the miRNA to its site of action, i.e., its target mRNA. (4) Binding of the miRNA to the mRNA 3′ UTR inhibits translation presumably at a point after translation initiation. (However, the nascent polypeptide chain (purple) exiting the ribosome in this model is solely for illustrative purposes, the presence of proteins stalled in elongation has not been demonstrated.) Downregulation of translation is thought to involve additional cofactors that presumably recognize the bulged-out nucleotides of the mRNA/stRNA duplexes.