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Review
. 2013 Nov;14(11):699-712.
doi: 10.1038/nrm3679. Epub 2013 Oct 9.

RNA in unexpected places: long non-coding RNA functions in diverse cellular contexts

Sarah Geisler  1 , Jeff Coller
Affiliations
Review

RNA in unexpected places: long non-coding RNA functions in diverse cellular contexts (VSports)

Sarah Geisler et al. Nat Rev Mol Cell Biol. 2013 Nov.

Abstract (V体育平台登录)

The increased application of transcriptome-wide profiling approaches has led to an explosion in the number of documented long non-coding RNAs (lncRNAs) VSports手机版. While these new and enigmatic players in the complex transcriptional milieu are encoded by a significant proportion of the genome, their functions are mostly unknown. Early discoveries support a paradigm in which lncRNAs regulate transcription via chromatin modulation, but new functions are steadily emerging. Given the biochemical versatility of RNA, lncRNAs may be used for various tasks, including post-transcriptional regulation, organization of protein complexes, cell-cell signalling and allosteric regulation of proteins. .

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Figures

Figure 1
Figure 1. RNA is a biochemically versatile polymer
a | RNA is particularly well suited for sequence-specific nucleic acid targeting through base pairing interactions over a short region (for example, eight nucleotides). By contrast, proteins require repeat motifs comprising 35–39 amino acids (105–117 base pairs of genomic sequence) to recognize a single RNA base with specificity. Therefore, to recognize eight nucleotides, 280–312 amino acids (840–936 base pairs of genomic sequence) would be required. Compared to the eight base pairs required for an RNA, protein-based nucleic acid recognition requires substantially more genomic sequence.b | RNA can fold into complex three-dimensional structures that can specifically bind various ligands, including small molecules and peptides.c | RNA is suitable for transient expression, because a fully functional RNA can be generated immediately following transcription and processing but can also be rapidly degraded. Together, this allows RNA effectors to be produced in quick pulses. Proteins, however, require additional steps, including mRNA export and translation, to produce a functional peptide. Likewise, both the mRNA and the protein need to be degraded to turn off expression, d | RNA is malleable and, therefore, more tolerant of mutations. Although some mutations in protein-coding genes are silent, many are deleterious such as nonsense mutations that generate truncated polypeptides. RNA, however, can tolerate mutations even within the regions responsible for target recognition. e | RNA-dependent events can be heritable. For instance, processed pseudogeneswere once RNA transcripts that have beengenomically integrated. In add it ion, telomerase uses an RNA template to add telomeric repeats to the ends of chromosomes. ORF, open reading frame; Pol II, RNA polymerase II.
Figure 2
Figure 2. lncRNAs regulate transcription through several mechanisms
a-c | Long non-coding RNAs (lncRNAs) can modulate chromatin through transcription-independent (part a) and transcription-dependent mechanisms (parts b and c). lncRNAs can bind one or more chromatin-modifying complexes and target their activities to specific DNA loci (part a). Depending on the nature of the enzymes bound, lncRNA-mediated chromatin modifications can activate or repress gene expression,,,,. Chromatin-modifying complexes bound to the RNA polymerase II (Pol II) carboxy-terminal domain (CTD) can modify chromatin during transcription of lncRNAs– (part b). Transcription of lncRNAs can also result in chromatin remodelling that can either favour or inhibit the binding of regulatory factors (part c). Depending on the nature of the factors that bind during remodelling, gene expression is activated or repressed –. d–g | lncRNAs can modulate both the general transcription machinery (parts d and e) as well as specific regulatory factors (parts f and g). lncRNAs can bind Pol II directly to inhibit transcription (part d). Formation of lncRNA-DNA triplex structures can also inhibit the assembly of the pre-initiation complex (part e). lncRNAs can fold into structures that mimic DNA-binding sites (left) orthat generally inhibit or enhance the activity of specific transcript ion factors (right)– (part f). lncRNAs can also regulate gene expression by binding specific transport factors to inhibit the nuclear localization of specific transcription factors (part g).
Figure 3
Figure 3. lncRNAs influence mRNA processing and post-transcriptional regulation
a,b | Long non-coding RNAs (lncRNAs) can modulate mRNA processing. Splicing patterns can be influenced by lncRNAs that associate with the pre-mRNA(part a). For example, splicing of the first intron of neuroblastoma MYC mRNA is prevented by a natural antisense transcript. Antisense lncRNAs that associate with an mRNA could direct mRNA editing, perhaps through association of the duplex with ADAR (adenosine deaminase acting on RNA) enzymes that catalyse adenosine to inosine conversion in double-stranded RNA, (part b). c-f | lncRNAs modulate post-transcriptional regulatory events. lncRNAs containing SIN EB2 repeat elements can upregulate translation through association with the 5′ region of an mRNA (part c). lncRNAs containing Alu repeat elements associate with the Alu elements in the 3′ untranslated region (UTR)of an mRNA, and this double-stranded structure can direct Staufen-mediated decaythrough a pathwaythat is molecularly similar to nonsense-mediated decay (part d). lncRNAs can mask miRNA-binding sites on a target mRNA to block miRNA-induced silencing through the RNA-induced silencing complex (RISC) (part e). Linear or circular lncRNAs can function as miRNA decoys to sequester miRNAs from their target mRNAs, (part f).
Figure 4
Figure 4. lncRNAsare involved in various cellular contexts
Long non-coding RNAs(lncRNAs) modulate protein activity by post-translational mechanisms (parts a-c). a | Small nucleolar lncRNAs(sno-lncRNAs) generated from the 15qll-ql3 locus bind and modulate the activity of the FOX2 alternative splicing factor, and this can inhibit FOX2-mediated splicing.b | The highly structured rncs-1 lncRNA binds Dicer to inhibit the processing of small RNAsc | The gadd 7 IncRN A binds and modulates the ability of TDP43 (TAR DNA-binding protein 43) to target and process specific mRNAs.d | lncRNAscan act as scaffolds to organize several complexes.e | As the cargo of exosomesthat mediate transfer of material between cells, exosomal shuttle RNAs(exRNAs)may act as signalling molecules during cell-cell communication; exosomal cargo includes mRN As, microRNAs (miRNAs) and lncRNAs.f | lncRNAs expressed from the switch region of genes encoding antibodies form R-loops to direct class switch recombinationvia activation-induced deaminase (AID) recruitment
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