Non-coding RNA: a new frontier in regulatory biology

Abstract

A striking finding in the past decade is the production of numerous non-coding RNAs (ncRNAs) from mammalian genomes. While it is entirely possible that many of those ncRNAs are transcription noises or by-products of RNA processing, increasing evidence suggests that a large fraction of them are functional and provide various regulatory activities in the cell. Thus, functional genomics and proteomics are incomplete without understanding functional ribonomics. As has been long suggested by the 'RNA world' hypothesis, many ncRNAs have the capacity to act like proteins in diverse biochemical processes. The enormous amount of information residing in the primary sequences and secondary structures of ncRNAs makes them particularly suited to function as scaffolds for molecular interactions. In addition, their functions appear to be stringently controlled by default via abundant nucleases when not engaged in specific interactions. This review focuses on the functional properties of regulatory ncRNAs in comparison with proteins and emphasizes both the opportunities and challenges in future ncRNA research.

Keywords: biological functions; experimental approaches; functional genomics; non-coding RNA; regulatory mechanisms; the RNA world.

Figure 1

Production of distinct classes of ncRNAs from mammalian genomes. Top: protein-coding (green lines) genes produce divergent PATs at the transcription start site. Certain exonic and intronic sequences have the capacity to generate circRNAs containing either 3′–5′ or 2′–5′ phosphodiester bonds. Many intronic sequences can also encode for miRNAs or snoRNAs. Genes for rRNAs, tR-NAs, or a subfraction of snRNAs are transcribed from separate genes. Bottom: similar to protein-coding genes, transcription enhancers also produce divergent transcripts, known as eRNAs. Most of the lncRNA genes contain at least one intron and are transcribed and processed in the same way as protein-coding genes except that they do not have coding potential (yellow line). miRNAs and piRNAs can also be derived from various intergenic regions.

Figure 2

Modes of ncRNA action on genomic DNA in regulated gene expression. lncRNAs are best characterized for their interactions with transcriptional regulators on functional DNA elements. (a) Various antisense transcripts, which appear to be quite widespread in humans and mice [42], may act as ncRNAs to interfere with Pol II elongation [41]. (b) Repeat-derived ncRNAs to block transcription. The prototype ncRNAs in this class are some transcribed Alu sequences, which bind to and interfere with Pol II function at gene promoters [44]. (c) A ncRNA may function as a decoy to compete for a specific transcription factor. The prototype for this mode is PANDA in sequestering the transcription factor NF-YA [45]. (d) A ncRNA may also facilitate the recruitment of a transcription regulator to a specific target site by engaging base-pairing interactions with genomic DNA. The prototype for this mode is the rRNA gene PATs [38]. (e) A ncRNA may bridge protein–protein interactions between transcription regulators to enhance their activities on a common DNA target. The prototype for this mode is the ncRNA HOTAIR in bridging PRC2 and the lysine demethylase LSD1 to mediate gene silencing [37]. (f) A ncRNA may mediate long-distance interactions between promoter and enhancer during transcription activation. Both cis-acting eRNAs and lncRNAs have been demonstrated to play such a role [40,46,47,51].

Figure 3

ncRNAs as integrated parts of gene networks. (a) ncRNAs mediate promoter–enhancer interactions to regulate the expression of various protein-coding genes. Protein-coding transcripts are also subjected to regulation by miRNAs to fine tune protein synthesis in the cytoplasm. (b) ncRNA genes produce various regulatory ncRNAs, which then participate in regulated expression of both protein-coding and non-coding genes. (c) ncRNAs may play a critical role in the organization of the genome in the nucleus to coordinate the expression of gene clusters. (d) Regulated gene expression at both the transcriptional and post-transcriptional levels determines the cell type-specific proteome and ncRNAs may also be extensively involved in protein interaction networks, which together contribute to gene networks in the cell.