Fine-tuning of microRNA-mediated repression of mRNA by splicing-regulated and highly repressive microRNA recognition element

Abstract

BackgroundMicroRNAs are very small non-coding RNAs that interact with microRNA recognition elements (MREs) on their target messenger RNAs. Varying the concentration of a given microRNA may influence the expression of many target proteins. Yet, the expression of a specific target protein can be fine-tuned by alternative cleavage and polyadenylation to the corresponding mRNA.ResultsThis study showed that alternative splicing of mRNA is a fine-tuning mechanism in the cellular regulatory network. The splicing-regulated MREs are often highly repressive MREs. This phenomenon was observed not only in the hsa-miR-148a-regulated DNMT3B gene, but also in many target genes regulated by hsa-miR-124, hsa-miR-1, and hsa-miR-181a. When a gene contains multiple MREs in transcripts, such as the VEGF gene, the splicing-regulated MREs are again the highly repressive MREs. Approximately one-third of the analysable human MREs in MiRTarBase and TarBase can potentially perform the splicing-regulated fine-tuning. Interestingly, the high (+30%) repression ratios observed in most of these splicing-regulated MREs indicate associations with functions. For example, the MRE-free transcripts of many oncogenes, such as N-RAS and others may escape microRNA-mediated suppression in cancer tissues.ConclusionsThis fine-tuning mechanism revealed associations with highly repressive MRE. Since high-repression MREs are involved in many important biological phenomena, the described association implies that splicing-regulated MREs are functional. A possible application of this observed association is in distinguishing functionally relevant MREs from predicted MREs.

Genome-wide identification of target genes for miR-204 and miR-211 identifies their proliferation stimulatory role in breast cancer cells

“…It is speculated that other factors cooperate with miRs to determine the scope of target genes and pathways in a given cell. The expression of a specific target protein can be fine-tuned by alternative cleavage and polyadenylation to the corresponding RNA 52 . Approximately one-third of the analyzable human miR recognition elements (MREs) in MiRTarBase and TarBase can potentially perform splicing-regulated fine-tuning.…”

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