Recently, a handful of intergenic long noncoding RNAs (lncRNAs) have been shown to compete with mRNAs for binding to miRNAs and to contribute to development and disease. Beyond these reports, little is yet known of the extent and functional consequences of miRNA-mediated regulation of mRNA levels by lncRNAs. To gain further insight into lncRNA-mRNA miRNA-mediated crosstalk, we reanalyzed transcriptome-wide changes induced by the targeted knockdown of over 100 lncRNA transcripts in mouse embryonic stem cells (mESCs). We predicted that, on average, almost one-fifth of the transcript level changes induced by lncRNAs are dependent on miRNAs that are highly abundant in mESCs. We validated these findings experimentally by temporally profiling transcriptome-wide changes in gene expression following the loss of miRNA biogenesis in mESCs. Following the depletion of miRNAs, we found that >50% of lncRNAs and their miRNA-dependent mRNA targets were up-regulated coordinately, consistent with their interaction being miRNA-mediated. These lncRNAs are preferentially located in the cytoplasm, and the response elements for miRNAs they share with their targets have been preserved in mammals by purifying selection. Lastly, miRNA-dependent mRNA targets of each lncRNA tended to share common biological functions. Post-transcriptional miRNA-mediated crosstalk between lncRNAs and mRNA, in mESCs, is thus surprisingly prevalent, conserved in mammals, and likely to contribute to critical developmental processes.
BackgroundRecent reports have highlighted instances of mRNAs that, in addition to coding for protein, regulate the abundance of related transcripts by altering microRNA availability. These two mRNA roles - one mediated by RNA and the other by protein - are inter-dependent and hence cannot easily be separated. Whether the RNA-mediated role of transcripts is important, per se, or whether it is a relatively innocuous consequence of competition by different transcripts for microRNA binding remains unknown.ResultsHere we took advantage of 48 loci that encoded proteins in the earliest eutherian ancestor, but whose protein-coding capability has since been lost specifically during rodent evolution. Sixty-five percent of such loci, which we term 'unitary pseudogenes', have retained their expression in mouse and their transcripts exhibit conserved tissue expression profiles. The maintenance of these unitary pseudogenes' spatial expression profiles is associated with conservation of their microRNA response elements and these appear to preserve the post-transcriptional roles of their protein-coding ancestor. We used mouse Pbcas4, an exemplar of these transcribed unitary pseudogenes, to experimentally test our genome-wide predictions. We demonstrate that the role of Pbcas4 as a competitive endogenous RNA has been conserved and has outlived its ancestral gene's loss of protein-coding potential.ConclusionsThese results show that post-transcriptional regulation by bifunctional mRNAs can persist over long evolutionary time periods even after their protein coding ability has been lost.
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