Non-coding Natural Antisense RNA: Mechanisms of Action in the Regulation of Target Gene Expression and Its Clinical Implications

Recent advances in high-throughput technologies have revealed that 75% of the human genome is transcribed to RNA, whereas only 3% of transcripts are translated into proteins. Consequently, many long non-coding RNAs (lncRNAs) have been identified, which has improved our understanding of the complexity of biological processes. LncRNAs comprise multiple classes of RNA transcripts that regulate the transcription, stability and translation of protein-coding genes in a genome. Natural antisense transcripts (NATs) form one such class, and the GENCODE v30 catalog contains 16193 lncRNA loci, of which 5611 are antisense loci. This review outlines our emerging understanding of lncRNAs, with a particular focus on how lncRNAs regulate gene expression using interferon-alpha 1 (IFN-alpha 1) mRNA and its antisense partner IFN-alpha 1 antisense (as) RNA as an example. We have identified and characterized the asRNA that determines post-transcriptional IFN-alpha 1 mRNA levels. IFN-alpha 1 asRNA stabilizes IFN-alpha 1 mRNA by cytoplasmic sense-antisense duplex formation, which may enhance the accessibility of an RNA stabilizer protein or decrease the affinity of an RNA decay factor for the RNA. IFN-alpha 1 asRNA can also act as competing molecules in the competing endogenous (ce)RNA network with other members of the IFNA multigene family mRNAs/asRNAs, and other cellular mRNA transcripts. Furthermore, antisense oligoribonucleotides representing functional domains of IFN-alpha 1 asRNA inhibit influenza virus proliferation in the respiratory tract of virus-infected animals. Thus, these findings support, at least in part, the rationale that dissecting the activity of NAT on gene expression regulation promises to reveal previously unanticipated biology, with potential to provide new therapeutic approaches to diseases.