The multidimensional mechanisms of long noncoding RNA function

Abstract

A major shift in our understanding of genome regulation has emerged recently. It is now apparent that the majority of cellular transcripts do not code for proteins, and many of them are long noncoding RNAs (lncRNAs). Increasingly, studies suggest that lncRNAs regulate gene expression through diverse mechanisms. We review emerging mechanistic views of lncRNAs in gene regulation in the cell nucleus. We discuss the functional interactions that lncRNAs establish with other molecules as well as the relationship between lncRNA transcription and function. While some of these mechanisms are specific to lncRNAs, others might be shared with other types of genes.

Fig. 1

The multiple dimensions of long noncoding RNA (lncRNA) function. lncRNAs can regulate gene expression by different mechanisms, some of which are illustrated here. These modes of action include lncRNA transcription-dependent activation or repression of neighbour genes (1), lncRNA-mediated inter-chromosomal interactions (2), formation of nuclear structures (i.e. paraspeckles) (3) or R-loops (4), lncRNAs as guide (5) or decoy (6) of transcription factors or as a scaffold for chromatin modifying complexes (7), lncRNAs acting as sponges of miRNAs (8), regulating post-transcriptional mRNA decay (9), regulating the cellular localization of RNA-binding proteins (RBPs) (10) or DNA-binding proteins (DBPs) (11)

Fig. 2

Long noncoding RNAs (lncRNAs) modulate protein activities. a The lnc-DC regulates gene expression through a mechanism of action that involves its translocation to the cytoplasm, where it interacts with phosphorylated STAT3 and prevents pY705-STAT3 dephosphorylation by the tyrosine phosphatase SHP1 [49]. b The lncRNAs ncRNA-a3 and ncRNA-a7 functionally and physically associate with the Mediator complex to promote gene expression of their respective target genes. Either ncRNA-a stimulates the kinase activity of the CDK8 subunit of the complex towards the histone H3, catalysing the phosphorylation of the serine 10 (H3S10) [53]. c CONCR functions in sister-chromatid cohesion by binding and promoting the ATPase activity of DDX11 during DNA replication [54]

Fig. 3

Long noncoding RNAs (lncRNAs) regulate gene expression by interacting with DNA-binding proteins. a The lncRNA GAS5 interacts with the activated glucocorticoid receptor (GR), which, following the binding of its ligand and the lncRNA, dissociates from heat-shock proteins (HSPs) and translocates to the nucleus. GAS5–GR interaction prevents GR from binding to the glucocorticoid-response elements (GRE) contained in responsive genes [58]. b DNA-damage-activated tumour suppressor protein p53 induces the transcription of the lncRNA DINO, which, in turn, binds and stabilizes p53, promoting the binding of the transcription factor to the p53-response elements (PRE) of target genes [59]

Fig. 4

Gene regulation linked to long noncoding RNA (lncRNA) transcription. a Airn transcription reduces the recruitment of RNAPII to the Igf2r promoter, a mechanism known as ‘transcriptional interference’, causing the silencing of the maternal Igf2r gene. Transcriptional overlap does not occur at the other imprinted genes in the Igf2r cluster—Slc22a2 and Slc22a3—where the silencing properties of Airn might reside in its RNA [97, 98]. b Cdkn1b expression is positively regulated by a cis-element of the genomic locus of Lockd, whereas the lncRNA is dispensable for this function [99]

Fig. 5

Long noncoding RNAs (lncRNAs) in genome architecture. a The lncRNA Firre is transcribed from the X chromosome (chrX) and, by binding hnRNP-U, acts as a platform for trans-chromosomal interactions [107]. b The lncRNA NEAT1 functions as an essential structural determinant for the assembly of paraspeckles. The nucleation process begins during the biogenesis of the lncRNA, which acts as a scaffold for the binding of paraspeckle proteins and RNAs, including adenosine to inosine edited RNAs [111, 114]