The Natural Antisense Transcript-Targeted Regulation Technology Using Sense Oligonucleotides and Its Application

Abstract

Natural antisense transcripts (NATs or AS transcripts) are frequently transcribed from many eukaryotic genes and post-transcriptionally regulate gene expression. The AS transcript is classified as noncoding RNA and acts as a regulatory RNA in concert with RNA-binding proteins that bind to cis-controlling elements on the mRNA, microRNAs, and drugs. The AS transcript that overlaps with mRNA regulates mRNA stability by interacting with mRNA, and the network of mRNAs, AS transcripts, microRNAs, and RNA-binding proteins finely tunes the output of gene regulation, i.e., mRNA levels. We found that single-stranded 'sense' oligonucleotides corresponding to an mRNA sequence decreased the mRNA levels by interfering with the mRNA-AS transcript interactions of several genes, such as inducible nitric oxide synthase (iNOS) and interferon-alpha1 (IFN-A1) genes. In contrast, AntagoNAT oligonucle-otides, which are complementary to AS transcripts, are sense oligonucleotides when they overlap with mRNA, but they increase the levels of specific mRNAs. Collectively, the sense oligonucleotide is a powerful tool for decreasing or increasing mRNA levels. The natural antisense transcript-targeted regulation (NATRE) technology using sense oligonucleotides is a method with a unique modality for modulating cytosolic mRNA levels and may be used to treat human diseases in which AS transcripts are involved.