The lin-4 microRNA

MicroRNAs (miRNAs) are full of surprises. The more we study these ~22-nucleotide non-coding RNAs, the more we realize how little is understood about this mode of gene regulation. 1 Case in point: lin-4, the founding member of the miRNA superfamily discovered over 20 years ago. Thousands of miRNAs have since been discovered in plant, animal, and viral genomes. They direct important cellular processes , such as proliferation, apoptosis, differentiation , metabolic and immune responses. Mounting evidence supports the canonical view that miRNAs function to block expression of their targets by associating in a sequence-specific manner to messenger RNA (mRNA) transcripts, causing mRNA degradation and/ or translational repression. A recent report by Turner et al. offers an expanded function for miRNAs in regulating gene expression. 2 Their work, focusing on lin-4, suggests that miRNAs can bind to their own promoters to induce their transcription—a process referred to as RNA activation (RNAa). Our fundamental understanding of miRNA mechanisms arose from studying lin-4 in the simple nematode Caenorhabditis elegans (C. elegans). early work by the Ambros and Ruvkun laboratories revealed lin-4 as the first gene in a cascade of factors required to direct post-embryonic proliferation and differentiation of hypodermal stem cells into specialized skin cells and egg-laying structures in the worm. 3 lin-4 is turned " on " at the end of the first of 4 larval stages (late L1) and binds to complementary regions in the 3′UTR of lin-14 and lin-28 to suppress their expression. Proper timing of lin-4 expression is critical to control the transition between the first and second larval stages during the nematode life cycle. Mutant worms lacking lin-4 reiterate cell fates normally seen in L1, which result in seam cell defects, absence of egg-laying structures, long body shape, and uncoordinated movement in adults. The question is, then, who is regulating the expression of lin-4, a master regulator of developmental timing in the worm? The control of lin-4 expression is complicated, involving both negative and positive factors (Fig. 1). The RNA binding protein RBM-28 promotes lin-4 activity by directing the processing of lin-4 precursor transcripts into biologically active mature miRNAs. 4 FLywCH Zn-finger transcription factors FLH-1 and FLH-2 bind directly to the lin-4 promoter and repress lin-4 transcription during embryogenesis, but somehow this repression is lifted in the larva at late L1. 5 work in this recent article by Turner et al. implicates lin-4 as the elusive positive transacting …