Abstract
BackgroundMicroRNAs (miRNAs) have the potential to regulate diverse sets of mRNA targets. In addition, mammalian genomes contain numerous natural antisense transcripts, most of which appear to be non-protein-coding RNAs (ncRNAs). We have recently identified and characterized a highly conserved non-coding antisense transcript for beta-secretase-1 (BACE1), a critical enzyme in Alzheimer's disease pathophysiology. The BACE1-antisense transcript is markedly up-regulated in brain samples from Alzheimer's disease patients and promotes the stability of the (sense) BACE1 transcript.ResultsWe report here that BACE1-antisense prevents miRNA-induced repression of BACE1 mRNA by masking the binding site for miR-485-5p. Indeed, miR-485-5p and BACE1-antisense compete for binding within the same region in the open reading frame of the BACE1 mRNA. We observed opposing effects of BACE1-antisense and miR-485-5p on BACE1 protein in vitro and showed that Locked Nucleic Acid-antimiR mediated knockdown of miR-485-5p as well as BACE1-antisense over-expression can prevent the miRNA-induced BACE1 suppression. We found that the expression of BACE1-antisense as well as miR-485-5p are dysregulated in RNA samples from Alzheimer's disease subjects compared to control individuals.ConclusionsOur data demonstrate an interface between two distinct groups of regulatory RNAs in the computation of BACE1 gene expression. Moreover, bioinformatics analyses revealed a theoretical basis for many other potential interactions between natural antisense transcripts and miRNAs at the binding sites of the latter.
Highlights
IntroductionMammalian genomes contain numerous natural antisense transcripts, most of which appear to be non-protein-coding RNAs (ncRNAs)
MicroRNAs have the potential to regulate diverse sets of mRNA targets
We showed that the same region of BACE1 mRNA may interact with a natural antisense transcript, BACE1-AS, and that there is potential for sense-antisense RNA duplex formation (Figure 1a, b)
Summary
Mammalian genomes contain numerous natural antisense transcripts, most of which appear to be non-protein-coding RNAs (ncRNAs). Recent transcriptomic efforts have revealed surprisingly large numbers of non-protein-coding RNAs (ncRNAs) in mammalian genomes [1,2,3,4]. We show that BACE1-AS prevents miRNA-induced translational repression and mRNA decay of BACE1 mRNA by 'masking' the binding site for miR-485-5p. Covering the miR-485-5p miRNA-binding site by BACE1-AS transcripts might eliminate miRNA-induced translational repression and BACE1 mRNA decay. Considering the reported effects of miRNAs on mRNA stability [16], cytoplasmic sense-antisense RNA duplex formation can potentially inhibit the interactions between miR-485-5p and BACE1 mRNA to explain, in part, the enhancement of BACE1 mRNA stability by BACE1-AS transcripts
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