Revealing Posttranscriptional Regulatory Elements Through Network-Level Conservation

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Abstract
We used network-level conservation between pairs of fly (Drosophila melanogaster/D. pseudoobscura) and worm (Caenorhabditis elegans/C. briggsae) genomes to detect highly conserved mRNA motifs in 3′ untranslated regions. Many of these elements are complementary to the 5′ extremity of known microRNAs (miRNAs), and likely correspond to their target sites. We also identify known targets of RNA-binding proteins, and many novel sites not yet known to be functional. Coherent sets of genes with similar function often bear the same conserved elements, providing new insights into their cellular functions. We also show that target sites for distinct miRNAs are often simultaneously conserved, suggesting combinatorial regulation by multiple miRNAs. A genome-wide search for conserved stem-loops, containing complementary sequences to the novel sites, revealed many new candidate miRNAs that likely target them. We also provide evidence that posttranscriptional networks have undergone extensive rewiring across distant phyla, despite strong conservation of regulatory elements themselves. Organisms have evolved extensive regulatory mechanisms for the appropriate expression of genes within precise spatiotemporal contexts. Until recently most of this regulation was thought to be implemented by processes that operate at the “transcriptional” level, that is, by modifying the rate at which mRNA is synthesized. The discovery of short RNAs, termed microRNAs (miRNAs), which can affect gene expression either by degradation of target mRNAs or by inhibiting their translation, has focused much recent effort on determining their specific functional roles and the extent to which they contribute to establishing protein repertoires within individual cells. Chan and colleagues have applied a computational comparative genomic approach for identifying the targets of these miRNAs within 3′ untranslated regions of mRNAs in closely related flies and worms. Their approach identifies a large number of target genes for most of the known miRNAs in these species, providing evidence that these regulators have a much more extensive role than previously thought. The sets of genes targeted by each miRNA are enriched in various known functional classes, providing strong clues for their role in physiology and development. The authors went on to identify many novel miRNAs based on the sequence of highly conserved target sites. They also found a large number of targets that do not correspond to miRNAs, some of which match the targets of known RNA-binding proteins. By comparing the large catalog of putative regulatory elements between flies and worms, they show that, although a large fraction of these elements are conserved, they are targeting, by and large, different sets of genes.