Transcriptional and Post-transcriptional Gene Regulation by Long Non-coding RNA

Abstract

Advances in genomics technology over recent years have led to the surprising discovery that the genome is far more pervasively transcribed than was previously appreciated. Much of the newly-discovered transcriptome appears to represent long non-coding RNA (lncRNA), a heterogeneous group of largely uncharacterised transcripts. Understanding the biological function of these molecules represents a major challenge and in this review we discuss some of the progress made to date. One major theme of lncRNA biology seems to be the existence of a network of interactions with microRNA (miRNA) pathways. lncRNA has been shown to act as both a source and an inhibitory regulator of miRNA. At the transcriptional level, a model is emerging whereby lncRNA bridges DNA and protein by binding to chromatin and serving as a scaffold for modifying protein complexes. Such a mechanism can bridge promoters to enhancers or enhancer-like non-coding genes by regulating chromatin looping, as well as conferring specificity on histone modifying complexes by directing them to specific loci.

Keywords: Epigenetics; Long non-coding RNA; MicroRNA; Post-transcriptional regulation; Transcriptional regulation.

Figure 1

lncRNA as a source of miRNA Many lncRNA genes contain embedded miRNA sequences (red boxes), which may be located within either an exon (blue box) or an intron (line) of the gene. Furthermore, miRNAs are encoded by independent transcriptional units and often occur in clusters within the genome. The three sources result in very different types of primary transcript but the pathways converge at the level of pre-miRNA structure. lncRNA, long non-coding RNA; miRNA, microRNA; pri-miRNA, primary miRNA; pre-miRNA, precursor miRNA.

Figure 2

The ceRNA hypothesis mRNA contains MREs (ovals), which are normally located within the 3′UTR. miRNA binding to the identical MREs may be present in a number of ncRNA species, including pseudogenes, circRNAs, other forms of lncRNA, and independently-transcribed mRNA 3′UTRs. All of these RNAs could potentially compete for a limited pool of miRNA, thus positively regulating gene expression. lncRNA and circRNA may carry MREs for multiple miRNAs (indicated by differently coloured ovals). MRE, miRNA response element; UTR, untranslated region; miRNA, microRNA; lncRNA, long non-coding RNA; circRNA, circular RNA; CDS, coding sequence; ceRNA, competing endogenous RNA.

Figure 3

Models of transcriptional regulation In the bridging scaffold model (A), activating RNAs (red line) are transcribed from enhancer-like non-coding genes and are required to recruit the mediator complex and to mediate chromatin conformational changes bridging the enhancer-like non-coding gene and the promoter of a coding gene. In the tethered scaffold model (B), lncRNA (red line) recognises specific DNA motifs and recruits histone modifying enzymes such as PRC2 to the locus. lncRNA, long non-coding RNA; PRC2, polycomb repressive complex 2; RNAPII, RNA polymerase II.