Natural antisense transcripts

Abstract

Recent years have seen the increasing understanding of the crucial role of RNA in the functioning of the eukaryotic genome. These discoveries, fueled by the achievements of the FANTOM, and later GENCODE and ENCODE consortia, led to the recognition of the important regulatory roles of natural antisense transcripts (NATs) arising from what was previously thought to be 'junk DNA'. Roughly defined as non-coding regulatory RNA transcribed from the opposite strand of a coding gene locus, NATs are proving to be a heterogeneous group with high potential for therapeutic application. Here, we attempt to summarize the rapidly growing knowledge about this important non-coding RNA subclass.

Figure 1.

Proposed mechanisms of NAT-mediated regulation. (A) Interaction with protein complexes: decoy mechanism. NAT binds to a protein complex, which either prevents RNApol binding to the coding gene's promoter and thus inhibits transcription or interferes with mRNA translation (not shown) (29,30). (B) Interaction with protein complexes: tethering mechanism. NAT is transcribed from the opposite strand of the protein-coding locus. The NAT-mediated tethering can occur by the nascent NAT at the time of NAT transcription or after NAT transcription has been completed, by pairing with DNA or nascent mRNA sequences. NAT then binds a protein complex (e.g. PRC2) thus tethering it to the coding gene locus, and/or scaffolding several proteins at the promoter site. PRC2 catalyzes the trimethylation of histone H3 at lysine 27 (H3K27me3), which is recognized by PRC1. PRC1 then catalyzes the monoubiquitylation of histone H2A, which contributes to chromatin compaction and repression of the target locus (2,31). (C) Generation of endogenous siRNAs and miRNA. NAT forms internal hairpins or duplexes with mRNA in the areas of homology. The double-stranded RNA stretches are trimmed by Dicer to form short RNA duplexes, which are then bound by the RISC complex and used as a template for recognition of mRNA. Captured mRNA is then cleaved by the RISC complex, reducing protein expression (32,33).