The functions and unique features of long intergenic non-coding RNA

Abstract

Long intergenic non-coding RNA (lincRNA) genes have diverse features that distinguish them from mRNA-encoding genes and exercise functions such as remodelling chromatin and genome architecture, RNA stabilization and transcription regulation, including enhancer-associated activity. Some genes currently annotated as encoding lincRNAs include small open reading frames (smORFs) and encode functional peptides and thus may be more properly classified as coding RNAs. lincRNAs may broadly serve to fine-tune the expression of neighbouring genes with remarkable tissue specificity through a diversity of mechanisms, highlighting our rapidly evolving understanding of the non-coding genome.

Figure 1. Distinguishing features of long intergenic non-coding RNAs (lincRNAs) and mRNAs

a | During transcription, some lincRNAs undergo cleavage and premature termination, whereas others are spliced and polyadenylated similarly to mRNAs. b | LincRNAs are generally more abundant in the nucleus, whereas mRNAs are generally more abundant in the cytoplasm, where they associate with ribosomes. LincRNAs and mRNAs have similar occupancy (residence) at the chromatin, whereas lincRNAs are relatively depleted in the nucleoplasm compared with mRNAs, possibly as a result of degradation by the nuclear exosome. Poorly processed lincRNAs may be targeted to the nuclear exosome for degradation at least partially by microprocessor complex subunit DGCR8, whereas those more similar to mRNAs may remain in the cytoplasm, where they are stable. Cytoplasmic lincRNAs and mRNAs can be degraded following 5ʹ decapping. c | LincRNA-coding and protein-coding genes have globally similar chromatin profiles^,. LincRNAs are distinguished by enrichment in histone H3 Lys9 trimethylation (H3K9me3) at their promoters. This is a canonically repressive mark, but in lincRNAs, it is instead associated with greater tissue specificity; the mechanism has not yet been described. H3K4me1 is associated with enhancers and H3K4me3 is associated with promoters. Pol II, RNA polymerase II; TSS, transcription start site.

Figure 2. Tissue specificity of long intergenic non-coding RNA (lincRNA) expression

a | We calculated the individual tau (tissue specificity) scores, which range from 0 to 1 (0 for uniform expression; 1 for single-tissue expression), of 7,842 lincRNAs (blue) and 22,285 mRNAs (red) across 30 human tissues from the GTEx Analysis v6 data set (dbGaP Accession phs000424.v6.p1 based on GENCODE v19 (hg19; July 2013)). We additionally calculated tau scores after permutation of each RNA to its assigned tissue to estimate the false discovery rate (FDR). The results are depicted as a violin plot of tau score distributions, demonstrating greater tissue specificity for lincRNAs than mRNAs (median 0.90 for lincRNA; 0.77 for mRNA; 0.47 for permutation; one-sided Wilcoxon test, ***P < 0.001). The white dots represent the median; thick and thin bars represent one or two standard deviations from the median, respectively. b | Proportion of lincRNAs and mRNAs that are tissue-specific by tau score. c | For each lincRNA with significant tissue specificity (tau >0.88; FDR <0.05 by permutation distribution), we re-calculated its tau score 30 additional times, each time excluding one tissue to estimate the individual contribution of the tissue. If tissue specificity no longer reached significance with exclusion of one tissue, we designated the lincRNA as specific to that tissue. Given that such a lincRNA may have tissue specificity through enrichment or depletion, we also calculated the direction of its contribution (one-sided Student’s t-test, P < 0.05). Shown is the number of lincRNAs with a distinct expression signature in a single tissue owing to enrichment (positive y axis) or depletion (negative y axis), which highlights the abundance of tissue-specific lincRNAs in the testis and brain.

Figure 3. The diverse functions of long intergenic non-coding RNAs (lincRNAs)

a | Regulation of chromatin structure and function in cis and in trans. HOTTIP associates with the myeloid/lymphoid or mixed-lineage leukaemia protein 1 (MLL1) complex, which catalyses histone H3 Lys4 trimethylation (H3K4me3) to activate HOTTIP transcription in cis (left). HOTAIR interacts in trans with the polycomb recessive complex 2 (PRC2) to mediate its deposition of the repressive H3K27me3 modification and with the KDM1A–CoREST–REST complex to mediate H3K4 demethylation, to coordinate transcription repression at target loci (right). b,c | LincRNAs scaffold proteins and RNAs in the nucleus and cytoplasm. b | TINCR binds Staufen1 in the cytoplasm, and binds and stabilizes mRNAs through its TINCR box motif to promote epidermal differentiation. c | In the presence of HuR, lincRNA-p21 is destabilized by recruitment of the microRNA (miRNA) let-7 in complex with Argonaute 2 (Ago2). HuR association with the lincRNA-p21 target mRNAs JUNB and CTNNB1 results in their translation. In the absence of HuR, lincRNA-p21 remains stable, accumulates and associates with the JUNB and CTNNB1 transcripts in a mechanism that is at least partially mediated by co-association with the RNA-binding protein Rck and represses their translation by decreasing their ribosome association. d,e | LincRNAs act as protein and RNA decoys. d | The expression of the lincRNA Gas5 is induced by growth arrest. Gas5 mimics the glucocorticoid response element (GRE) and binds the DNA-binding domain of the glucocorticoid receptor (GR), which sequesters the glucocorticoid receptor from its target genes. e | Linc-RoR is abundant in pluripotent stem cells, where it acts as a decoy of the miRNA miR-145, thereby inhibiting the targeting and downregulation of the mRNAs of the pluripotency factors octamer-binding protein 4 (OCT4), the transcription factor SOX2 and homeobox protein Nanog. As linc-RoR levels decrease during differentiation, miR-145 is released and mediates the degradation of its targets to promote differentiation. Part a is from REF. , Macmillan Publishers Limited.

Figure 4. Long intergenic non-coding RNAs (lincRNAs) that function through their transcriptional and translational activity

a | LincRNAs can regulate neighbouring genes by sequence-independent regulatory functions. In mice, splicing of the 5′ end of the lincRNA Blustr as well as general transcriptional activity at the Blustr locus activate the transcription of the upstream locus Sfmbt2, possibly by recruiting cofactors, accumulation of pro-transcription proteins and chromatin alteration. b | Some lincRNAs encode micropeptides. A conserved, small open reading frame (smORF) in the lincRNA LINC00961 produces the peptide small regulatory polypeptide of amino acid response (SPAR). In the presence of amino acids, SPAR interacting with the Ragulator complex impairs the recruitment of mTORC1 to the lysosome and thus inhibits mTORC1 activation. c | In the absence of ultraviolet irradiation, ASCC3 is efficiently transcribed to produce a long, coding transcript that produces the ASCC3 protein, which is a component of the ASCC complex that represses ultraviolet-induced DNA damage repair. Ultraviolet irradiation leads to slower transcription at the ASCC3 locus and induces the use of an alternative, proximal last exon and the expression of a short, non-coding RNA. This non-coding RNA antagonizes the function of the ASCC complex, thereby promoting recovery from ultraviolet-induced DNA damage. Pol II, RNA polymerase II; U1, U1 small nuclear RNA.