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.
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.