Article series: Non-coding RNA

Unique features of long non-coding RNA biogenesis and function

Journal name:
Nature Reviews Genetics
Volume:
17,
Pages:
47–62
Year published:
DOI:
doi:10.1038/nrg.2015.10
Published online

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.

At a glance

Figures

  1. The busy lifetimes of certain lncRNAs differ from those of mRNAs [mdash] in birth, life and death.
    Figure 1: The busy lifetimes of certain lncRNAs differ from those of mRNAs — in birth, life and death.

    Some long non-coding RNAs (lncRNAs) or classes of lncRNAs are regulated differentially at different points of their biogenesis, maturation and degradation. a | At the level of the chromatin state, lncRNAs and mRNAs exhibit similar properties, such as an enrichment of H3K4me3 at promoters; however, lncRNA genes have a higher enrichment of H3K27ac and are more strongly repressed by certain chromatin remodelling complexes, such as Swr1, Isw2, Rsc and Ino80. b | Transcriptional initiation from divergent promoters differs for the sense (mRNA) and the antisense (lncRNA) directions; divergent antisense transcription is enriched for H3K56ac and phosphorylation of RNA polymerase II (Pol II) Tyr1. Transcription in the divergent direction is further enhanced by the SWI/SNF proteins and repressed by CAF-1. c | Transcriptional elongation is more strongly regulated by DICER1 and MYC for lncRNAs than for mRNAs. d | The occurrence of U1 and polyadenylation signals differs on either side of bidirectional promoters (along the U1–PAS axis), favouring the splicing of mRNAs in the sense direction and the cleavage and polyadenylation in the divergent, antisense direction. e | Whereas mRNAs localize very specifically to ribosomes in the cytoplasm, lncRNA localization is much more varied, as certain lncRNAs can occupy the chromatin, subnuclear domains, the nucleoplasm or the cytoplasm. f | Finally, whereas mRNAs are primarily degraded in the cytoplasm by decapping and 5′-to-3′ exonuclease digestion, many unstable lncRNA transcripts are subject to the nuclear exosome or to cytosolic nonsense-mediated decay (NMD). TSS, transcription start site.

  2. Post-transcriptional processing events in special lncRNA classes.
    Figure 2: Post-transcriptional processing events in special lncRNA classes.

    a,b | Many long non-coding RNAs (lncRNAs) undergo special processing events that have not been observed in mRNAs. For example, MALAT1 (metastasis-associated lung adenocarcinoma transcript 1) and NEAT1 (nuclear enriched abundant transcript 1) lncRNAs are processed at their 3′ ends by RNase P, which generates tRNA-like small RNA products and the mature lncRNA, which possesses a stabilizing 3′-terminal RNA triplex structure; MALAT1 is localized to nuclear speckles and NEAT1 is localized to nuclear paraspeckles; the tRNA-like structures cleaved from MALAT1 (mascRNAs) are stable and cytoplasmic, whereas those from NEAT1 are unstable. c | Canonical splicing of mRNAs produces linear transcripts but back-splicing produces stable circular RNAs (circRNAs) consisting of non-sequential exon–exon junctions. d | Intronic lariats are typically unstable after splicing, but some escape debranching and degradation and persist as non-coding circular intronic long non-coding RNAs (ciRNAs). e | sno-lncRNAs are derived from the introns of small nucleolar RNA (snoRNA) host genes and are flanked by snoRNAs instead of 5′ caps or poly(A)-tails. f | Whereas many microRNA (miRNA) genes are found within the introns of protein-coding genes (right), some lncRNAs host miRNA genes, which are processed by Microprocessor instead of the traditional cleavage and polyadenylation pathway (left). Pol II, RNA polymerase II.

  3. Cis-regulatory mechanisms of lncRNA function.
    Figure 3: Cis-regulatory mechanisms of lncRNA function.

    a | Long non-coding RNAs (lncRNAs) are uniquely poised to regulate their genomic neighbourhoods in cis. Some enhancer RNAs, such as LUNAR1 near the insulin-like growth factor 1 receptor (IGF1R) locus, mediate chromosome looping between enhancers and nearby target genes via Mediator or MLL protein complexes. b | PcG response element/TrxG response element (PRE/TRE) enhancer RNAs can switch between silencing and activating states by switching bidirectional transcription; forward transcription of one such PRE/TRE represses vestigial expression via Polycomb group (PcG), whereas transcription in the reverse direction activates vestigial expression via Trithorax group (TrxG). c | Allele-specific DNA methylation at imprinted genomic loci silences the expression of lncRNAs within the imprinted gene cluster, thereby allowing neighbouring protein-coding genes to be expressed; conversely, on the other allele the lncRNA is expressed in the absence of DNA methylation, thereby repressing protein-coding genes in cis. d | The mammalian dosage compensation lncRNA, Xist, is silenced on the active X chromosome in cis by the antisense lncRNA Tsix; meanwhile, Xist is activated on the inactive X chromosome in cis and in trans by the lncRNA Jpx. e | ANRIL antisense lncRNA represses the cyclin-dependent kinase inhibitor 2A (CDKN2A)–CDKN2B locus in cis by recruiting PRC1 and PRC2. f | When protein-coding genes and antisense lncRNA genes overlap, processing RNA polymerase II (Pol II) particles may collide and thus abort transcription, effectively inhibiting the expression of both genes. g | FMR1 (fragile X mental retardation 1) binds and silences its own promoter via RNA–DNA hybrids at CGG repeat expansions that are characteristic of disease. h | roX1 in male Drosophila spp. autoregulates its own locus and sustains its own transcription by recruiting the activating dosage compensation complex (DCC).

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Affiliations

  1. Center for Personal Dynamic Regulomes, Stanford University School of Medicine, Stanford, California 94305, USA.

    • Jeffrey J. Quinn &
    • Howard Y. Chang
  2. Department of Bioengineering, Stanford University School of Medicine and School of Engineering, Stanford, California 94305, USA.

    • Jeffrey J. Quinn

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The authors declare no competing interests.

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  • Jeffrey J. Quinn

    Jeffrey J. Quinn is a graduate student in the laboratory of Howard Y. Chang at Stanford University, California, USA. He received his B.S. in biological engineering from Massachusetts Institute of Technology (MIT), Cambridge, USA, and is currently completing his Ph.D. in bioengineering at Stanford University. His current research concerns the molecular mechanisms and evolution of the long non-coding RNAs (lncRNAs) that are involved in dosage compensation, particularly focusing on the roX lncRNAs in Drosophila species.

  • Howard Y. Chang

    Howard Y. Chang is the director of the Center for Personalized Dynamic Regulomes and Professor of Dermatology at Stanford University School of Medicine, California, USA. He earned his Ph.D. in biology from Massachusetts Institute of Technology (MIT), Cambridge, USA, and M.D. from Harvard Medical School, Boston, Massachusetts, USA. The long-term goal of his research is to decipher the regulatory information in the human genome for disease diagnosis and therapy. Howard Y. Chang's laboratory homepage

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