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  • Review Article
  • Published:

Unique features of long non-coding RNA biogenesis and function

Key Points

  • Although long non-coding RNAs (lncRNAs) and mRNAs share many common features, several types of lncRNAs are distinguished from mRNAs by unique features of biogenesis, form and function.

  • lncRNAs exhibit more highly specific expression patterns than mRNAs.

  • Many lncRNAs undergo special processing events, such as backspliced circularization, 5′- and 3′-bookending by processed small nucleolar RNAs (snoRNAs), and cleavage by RNase P.

  • lncRNAs are more enriched in the nucleus than the cytoplasm relative to mRNAs, and although cytoplasmic lncRNAs associate with the ribosome, few are productively translated.

  • Certain classes of lncRNAs are preferentially subject to degradation by nonsense-mediated decay and the nuclear exosome, and the elongation of divergent ncRNA transcripts is co-transcriptionally terminated by premature polyadenylation.

  • lncRNAs are uniquely capable of cis action on the genome and chromatin. This feature of lncRNAs enables such biological phenomena as gene imprinting, dosage compensation of sex chromosomes, transcriptional enhancement, chromosome looping and antisense regulation.

Abstract

Long non-coding RNAs (lncRNAs) are a diverse class of RNAs that engage in numerous biological processes across every branch of life. Although initially discovered as mRNA-like transcripts that do not encode proteins, recent studies have revealed features of lncRNAs that further distinguish them from mRNAs. In this Review, we describe special events in the lifetimes of lncRNAs — before, during and after transcription — and discuss how these events ultimately shape the unique characteristics and functional roles of lncRNAs.

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Figure 1: The busy lifetimes of certain lncRNAs differ from those of mRNAs — in birth, life and death.
Figure 2: Post-transcriptional processing events in special lncRNA classes.
Figure 3: Cis-regulatory mechanisms of lncRNA function.

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Acknowledgements

The authors thank P. J. Batista, R. A. Flynn and G. X. Zheng for constructive discussions and comments on this Review. Supported by US National Institutes of Health grants, HHMI (H.Y.C.), and the Stanford Bio-X Fellowship (J.J.Q.). The authors apologize to colleagues whose work could not be cited or discussed owing to space constraints.

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FURTHER INFORMATION

GENCODE

PowerPoint slides

Glossary

Long non-coding RNAs

(lncRNAs). RNA transcripts with a length of >200 nt that do not encode proteins.

Imprinting

An epigenetic mechanism of regulating gene expression in an allele-specific manner.

Cis or trans

Long non-coding RNAs can act on their neighbouring genomic environment (in cis) or diffuse to distant sites of action (in trans).

Transcriptional noise

A hypothesis explaining pervasive transcription by which RNA polymerase II randomly initiates transcription throughout the genome.

Biogenesis

The production by organisms of new biological material, such as RNAs, proteins or organelles.

Open reading frames

(ORFs). Continuous stretches of codons that have the potential to encode a protein.

MicroRNAs

(miRNAs). Short (~22 nt) non-coding RNAs that post-transcriptionally silence target RNAs by base pairing.

Small nucleolar RNAs

(snoRNAs). A class of small RNAs that guide the chemical modification of ribosomal RNAs, tRNAs and others.

Ribosome profiling

A biochemical technique for mapping ribosome-associated and translated RNAs.

Chromatin

The compartment of the nucleus that compacts and organizes genomic DNA and regulates gene expression.

Divergent transcription

The production of sense and antisense RNAs from bidirectional promoters.

U1 snRNP

A ribonucleoprotein complex that coordinates the precise splicing of nascent RNA transcripts.

Enhancers

DNA-encoded elements that activate the expression of nearby genes.

RNase P

A ribonucleoprotein complex that cleaves tRNA precursors during their maturation.

Secondary structure

The base-pairing interactions that dictate nucleic acid folds.

Circular RNAs

(circRNAs). Chemically circular RNAs produced by nonsequential exon–exon back-splicing.

Circular intronic long non-coding RNAs

(ciRNAs). Circular, branched intronic RNAs resulting from stabilized introns after canonical splicing.

Exon-intron circRNAs

(EIciRNAs). A class of circular RNAs that retain unspliced introns.

sno-lncRNA

Long non-coding RNAs that are capped on the 5′ and 3′ ends by processed small nucleolar RNAs.

Bifunctional RNAs

RNAs with separable non-coding and protein-coding functions.

Nonsense-mediated decay

(NMD). A genetic pathway for the elimination of RNAs that are defective in protein coding, primarily owing to premature stop codons.

Exosome

A large protein complex that degrades RNA.

Upstream antisense RNAs

(uaRNAs). Non-coding RNAs transcribed in the opposite direction from promoters by divergent transcription.

Enhancer RNAs

(eRNAs). Non-coding RNAs transcribed from enhancers.

Dosage compensation

The epigenetic process of balancing gene expression from sex chromosomes between males and females.

DNA methylation

The chemical modification of cytosine residues on DNA that can be epigenetically inherited.

CpG island

DNA sites of the sequence CG where the cytosine may be methylated in a regulated manner.

Chromatin isolation by RNA purification

(ChIRP). A biochemical technique for mapping the genomic binding sites of an RNA of interest.

Synteny

The physical proximity of genes within a single genomic locus.

CRISPRi and CRISPRa

Sequence-specific interference (i) or activation (a) of gene expression using CRISPR technology. Typically, this involves a nuclease-deficient Cas9-mutant protein fused to transcriptional activator or repressor proteins; this fusion protein is then directed to a target genomic locus by an engineered guide RNA.

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Quinn, J., Chang, H. Unique features of long non-coding RNA biogenesis and function. Nat Rev Genet 17, 47–62 (2016). https://doi.org/10.1038/nrg.2015.10

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