Natural Antisense Transcripts at the Interface between Host Genome and Mobile Genetic Elements

Abstract

Non-coding RNAs are involved in epigenetic processes, playing a role in the regulation of gene expression at the transcriptional and post-transcriptional levels. A particular group of ncRNA are natural antisense transcripts (NATs); these are transcribed in the opposite direction to protein coding transcripts and are widespread in eukaryotes. Their abundance, evidence of phylogenetic conservation and an increasing number of well-characterized examples of antisense-mediated gene regulation are indicative of essential biological roles of NATs. There is evidence to suggest that they interfere with their corresponding sense transcript to elicit concordant and discordant regulation. The main mechanisms involved include transcriptional interference as well as dsRNA formation. Sense-antisense hybrid formation can trigger RNA interference, RNA editing or protein kinase R. However, the exact molecular mechanisms elicited by NATs in the context of these regulatory roles are currently poorly understood. Several examples confirm that ectopic expression of antisense transcripts trigger epigenetic silencing of the related sense transcript. Genomic approaches suggest that the antisense transcriptome carries a broader biological significance which goes beyond the physiological regulation of the directly related sense transcripts. Because NATs show evidence of conservation we speculate that they played a role in evolution, with early eukaryotes gaining selective advantage through the regulatory effects. With the surge of genome and transcriptome sequencing projects, there is promise of a more comprehensive understanding of the biological role of NATs and the regulatory mechanisms involved.

Keywords: DNA methylation; RNA interference; double stranded RNA (dsRNA); gene expression regulation; histone modifications; natural antisense transcripts; non-coding RNA.

FIGURE 1

Schematic representation of sense and antisense transcripts from bi-directionally transcribed loci. Commonly used descriptions are head-to-head, tail-to-tail, embedded and intronic (from top). The percent representation in the human genome is from Balbin et al. (2015). Importantly, transcripts in tail-to-tail and full overlap configuration potentially form double-stranded RNA whereas the other two categories do not. Other terms used are ‘convergent’ (tail-to-tail), divergent (head-to-head), or ‘non-overlapping’ (embedded).

FIGURE 2

Mechanisms of gene regulation involving natural antisense transcripts. (A) Co-expression of sense and antisense transcripts in the same cell may cause dsRNA formation. RNA masking can have inhibitory as well as stimulatory consequences on the protein-coding sense mRNA expression, depending on the motif that is obstructed. Due to potential PKR activation dsRNA formation must either occur in specific cellular compartments or in specific cell types that do not rise an interferon response (germ cells and stem cells). Parts of the figure are modified from Wight and Werner (2013). (B) Transcriptional interference, where the expression of one transcript affects transcription of the opposite strand, can occur at several levels. Sense–antisense expression shows a discordant pattern, the majority as a result of antisense transcription induced chromatin changes (Weinberg and Morris, 2016).