Natural antisense transcripts as therapeutic targets

Abstract

At the turn of the 21st century, the central dogma of molecular biology was challenged by the unexpected discovery that only 1.2% of all genes transcribed from the human genome actually encode proteins. In fact, large-scale sequencing of the human and mouse genomes revealed that the other 99% is comprised of thousands of non-protein coding transcripts or ‘non-coding RNAs’ (ncRNA) that form complex and overlapping networks, and act as transcriptional and post-transcriptional regulators within various cells and tissues [1-3]. These are broadly classified, according to their sizes, into short (<200bp) and long ncRNAs (lncRNAs) [4]. Although short ncRNAs, in particular microRNAs (miRNAs), have now been extensively characterized [5], until recently less attention had been paid to the abundance of long non-coding transcripts, previously viewed by many as genomic junk or ‘dark matter’. However, observations that a significant number of lncRNAs are conserved across species, and are expressed in a regional, temporal and cell-specific manner, suggested that these transcripts could indeed have functional relevance [6]. Particularly within the last few years, lncRNAs have been attracting increasing interest, in light of growing evidence that they play key roles in a variety of cellular processes. In 2006, it was proposed that lncRNAs, such as the natural antisense transcripts (NATs), represented novel therapeutic targets to influence the expression of genes or pathways that were previously considered to be undruggable [7]. In the years since, not only have we developed a greater understanding as to how these RNA molecules exert their control, but this type of innovative thinking has also inspired the formation of new biotech companies. Here we describe the various regulatory functions of NATs, as well as their emerging links to disease, and focus on their continued promise as viable therapeutic targets.