Abstract
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.
Highlights
Recent reports have highlighted instances of mRNAs that, in addition to coding for protein, regulate the abundance of related transcripts by altering microRNA availability
Negative regulation of mRNA levels by miRNAs appears to be widespread among eukaryotes and involves the recognition and binding of mature miRNAs to miRNA response elements (MREs) that are often located in the 3’ untranslated regions of target mRNAs [4,5,6]. miRNAs are largely preserved in animal evolution [7] and mutations in either microRNA response element (MRE) or miRNAs have been associated with gene expression changes
Predictions were visually inspected to ensure that: 1) frame-shifting indels or premature stop codon mutations were specific to both rodents; and 2) chromosomal gene order for genes immediately upstream and downstream of the lineage-specific unitary pseudogene was conserved in all four species [33,34]
Summary
Recent reports have highlighted instances of mRNAs that, in addition to coding for protein, regulate the abundance of related transcripts by altering microRNA availability. The protein-coding and miRNAmediated roles of mRNAs are not independent: targeting of miRNAs to a transcript’s MREs can result in decrease levels of its encoded protein and mRNA abundance will regulate, through competition for miRNAs, the levels of other transcripts [1,16,17]. It is this coupling between RNA- and protein-dependent functions of a transcript that renders the biological importance and implications of ceRNAs so difficult to determine. Whether these noncoding ceRNAs have other functions - for example, with additional transcriptional or chromatin regulation roles [19] remains to be established
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