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

Key Points

  • Long non-coding RNAs (lncRNAs), which constitute a substantial fraction of mammalian transcriptomes, are new, enigmatic players in the complex transcriptional milieu.

  • RNA is a versatile molecule that is well suited for a myriad of functions. This versatility stems from adeptness of RNA at sequence-specific nucleic acid recognition, its ability to fold into intricate three-dimensional structures, as well as its dynamic and malleable nature.

  • lncRNAs directly and indirectly regulate transcription. Specifically, lncRNAs both positively and negatively influence transcription by modulating chromatin, acting as enhancers, regulating transcription factor function and organizing nuclear domains.

  • lncRNAs regulate mRNA processing by modulating pre-mRNA splicing and have the potential to direct mRNA editing. Additionally, lncRNAs modulate other post-transcriptional events such as translation, mRNA stability and miRNA-mediated repression.

  • lncRNAs can act as scaffolds to organize multiprotein complexes and subnuclear domains.

  • With lncRNAs now found in exosomes, lncRNAs have the potential to function as signalling molecules. In addition, lncRNAs can increase genetic diversity by determining the sites of recombination.

Abstract

The increased application of transcriptome-wide profiling approaches has led to an explosion in the number of documented long non-coding RNAs (lncRNAs). 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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Figure 1: RNA is a biochemically versatile polymer.
Figure 2: lncRNAs regulate transcription through several mechanisms.
Figure 3: lncRNAs influence mRNA processing and post-transcriptional regulation.
Figure 4: lncRNAs are involved in various cellular contexts.

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Acknowledgements

The authors are most grateful to T. Nilsen and K. Baker for insights and suggestions. The authors regret that not all contributions of their colleagues could be discussed due to space constraints. Work in the authors' laboratory is funded by the National Institute of General Medical Sciences (NIGMS) (GM080465).

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Correspondence to Sarah Geisler or Jeff Coller.

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Glossary

Chromatin

Condensed DNA structure that is associated with histone proteins and other DNA-binding proteins.

Transcription activator-like effectors

(TALEs). Naturally found in some bacteria, TALEs are proteins that bind DNA through repeat domains, and their code for sequence specificity has been elucidated allowing sequence specific TALEs to be engineered.

PUF proteins

A family of sequence-specific RNA-binding proteins, which bind 3′ untranslated regions within mRNAs to repress target mRNA translation.

Pseudogenes

Dysfunctional relatives of normal genes thought to arise from duplication or retrotransposition.

Chromatin-modifying complexes

Protein complexes that catalyse the covalent chemical modification of chromatin.

Enhancers

Short regions of DNA that enhance the expression of genes at varying distances. Effects can be mediated by transcription factor binding to these sites.

Alu SINE elements

Highly abundant retrotransposons of the short interspersed nuclear elements (SINE) family.

Nuclear subdomains

Non-membrane bound subcompartments of eukaryotic nuclei where factors with similar functions colocalize.

GAL locus

An inducible locus in yeast comprising the GAL1 and GAL10 genes, which are required for galactose metabolism.

Alternative splicing

An mRNA processing step whereby exons can be alternatively used to generate different isoforms of the same gene.

Internal ribosome entry sites

(IRESs). Nucleotide sequence that allows cap-independent translation initiation within the middle of an mRNA transcript.

Spliceosome

The macromolecular machinery (composed of both RNA and protein) responsible for pre-mRNA splicing.

miRNAs

(miRNAs). A class of short (23 nucleotides) endogenous non-coding RNAs that control gene expression post-transcriptionally through either translational repression or mRNA degradation.

Competing endogeneous RNA

(ceRNA). RNA transcripts (both coding and non-coding), which share microRNA-targeting sites and thus regulate each other via direct competition for microRNA binding.

Circular RNA

(circRNA). As opposed to conventional linear RNA transcripts, the 5′ and 3′ ends of circular RNAs are covalently linked together.

Small nucleolar RNA

(snoRNA). A class of small RNA molecules that guide the chemical modification of other RNA transcripts.

sno-lncRNAs

(small nucleolar long non-coding RNAs). Class of intron-derived long non-coding RNA flanked by snoRNA ends.

Dicer

An RNase III family endoribonuclease responsible for the processing of pre-miRNAs into short double-stranded RNAs to be loaded into the RNA-induced silencing (RISC) complex.

Adaptive immune system

A system of specialized cells that create immunological memory via specific antibodies after an initial response to a pathogen.

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Geisler, S., Coller, J. RNA in unexpected places: long non-coding RNA functions in diverse cellular contexts. Nat Rev Mol Cell Biol 14, 699–712 (2013). https://doi.org/10.1038/nrm3679

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