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Long non-coding RNAs: insights into functions

Nature Reviews Genetics volume 10, pages 155–159 (2009)Cite this article

Abstract

In mammals and other eukaryotes most of the genome is transcribed in a developmentally regulated manner to produce large numbers of long non-coding RNAs (ncRNAs). Here we review the rapidly advancing field of long ncRNAs, describing their conservation, their organization in the genome and their roles in gene regulation. We also consider the medical implications, and the emerging recognition that any transcript, regardless of coding potential, can have an intrinsic function as an RNA.

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Figure 1: Genomic organization of coding and non-coding transcripts.
Figure 2: Functions of long non-coding RNAs (ncRNAs).

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References

  1. Carninci, P. et al. The transcriptional landscape of the mammalian genome. Science 309, 1559–1563 (2005).

    Article  CAS  Google Scholar 

  2. Denoeud, F. et al. Prominent use of distal 5′ transcription start sites and discovery of a large number of additional exons in ENCODE regions. Genome Res. 17, 746–759 (2007).

    Article  CAS  Google Scholar 

  3. Horiuchi, T. & Aigaki, T. Alternative trans-splicing: a novel mode of pre-mRNA processing. Biol. Cell 98, 135–140 (2006).

    Article  CAS  Google Scholar 

  4. Kapranov, P. et al. RNA maps reveal new RNA classes and a possible function for pervasive transcription. Science 316, 1484–1488 (2007).

    Article  CAS  Google Scholar 

  5. Kapranov, P. et al. Examples of the complex architecture of the human transcriptome revealed by RACE and high-density tiling arrays. Genome Res. 15, 987–997 (2005).

    Article  CAS  Google Scholar 

  6. Okazaki, Y. et al. Analysis of the mouse transcriptome based on functional annotation of 60,770 full-length cDNAs. Nature 420, 563–573 (2002).

    Article  Google Scholar 

  7. Struhl, K. Transcriptional noise and the fidelity of initiation by RNA polymerase II. Nature Struct. Mol. Biol. 14, 103–105 (2007).

    Article  CAS  Google Scholar 

  8. Amaral, P. P. & Mattick, J. S. Noncoding RNA in development. Mamm. Genome 19, 454–492 (2008).

    Article  CAS  Google Scholar 

  9. Dinger, M. E. et al. Long noncoding RNAs in mouse embryonic stem cell pluripotency and differentiation. Genome Res. 18, 1433–1445 (2008).

    Article  CAS  Google Scholar 

  10. Mercer, T. R., Dinger, M. E., Sunkin, S. M., Mehler, M. F. & Mattick, J. S. Specific expression of long noncoding RNAs in the adult mouse brain. Proc. Natl Acad. Sci. USA 105, 716–721 (2008).

    Article  CAS  Google Scholar 

  11. Cawley, S. et al. Unbiased mapping of transcription factor binding sites along human chromosomes 21 and 22 points to widespread regulation of noncoding RNAs. Cell 116, 499–509 (2004).

    Article  CAS  Google Scholar 

  12. Ponjavic, J., Ponting, C. P. & Lunter, G. Functionality or transcriptional noise? Evidence for selection within long noncoding RNAs. Genome Res. 17, 556–565 (2007).

    Article  CAS  Google Scholar 

  13. Guttman, M. et al. Chromatin signature reveals over a thousand highly conserved large non-coding RNAs in mammals. Nature (in the press).

  14. Pang, K. C., Frith, M. C. & Mattick, J. S. Rapid evolution of noncoding RNAs: lack of conservation does not mean lack of function. Trends Genet. 22, 1–5 (2006).

    Article  CAS  Google Scholar 

  15. Pollard, K. S. et al. An RNA gene expressed during cortical development evolved rapidly in humans. Nature 443, 167–172 (2006).

    Article  CAS  Google Scholar 

  16. Carroll, S. B. Evo–devo and an expanding evolutionary synthesis: a genetic theory of morphological evolution. Cell 134, 25–36 (2008).

    Article  CAS  Google Scholar 

  17. Hirota, K. et al. Stepwise chromatin remodelling by a cascade of transcription initiation of non-coding RNAs. Nature 456, 130–134 (2008).

    Article  CAS  Google Scholar 

  18. Torarinsson, E., Sawera, M., Havgaard, J. H., Fredholm, M. & Gorodkin, J. Thousands of corresponding human and mouse genomic regions unalignable in primary sequence contain common RNA structure. Genome Res. 16, 885–889 (2006).

    Article  CAS  Google Scholar 

  19. Mattick, J. S. & Gagen, M. J. The evolution of controlled multitasked gene networks: the role of introns and other noncoding RNAs in the development of complex organisms. Mol. Biol. Evol. 18, 1611–1630 (2001).

    Article  CAS  Google Scholar 

  20. Wilson, M. D. et al. Species-specific transcription in mice carrying human chromosome 21. Science 322, 434–438 (2008).

    Article  CAS  Google Scholar 

  21. Rinn, J. L. et al. Functional demarcation of active and silent chromatin domains in human HOX loci by noncoding RNAs. Cell 129, 1311–1323 (2007).

    Article  CAS  Google Scholar 

  22. Morris, K. V., Santoso, S., Turner, A. M., Pastori, C. & Hawkins, P. G. Bidirectional transcription directs both transcriptional gene activation and suppression in human cells. PLoS Genet. 4, e1000258 (2008).

    Article  Google Scholar 

  23. Nagano, T. et al. The Air noncoding RNA epigenetically silences transcription by targeting G9a to chromatin. Science 322, 1717–1720 (2008).

    Article  CAS  Google Scholar 

  24. Pandey, R. R. et al. Kcnq1ot1 antisense noncoding RNA mediates lineage-specific transcriptional silencing through chromatin-level regulation. Mol. Cell 32, 232–246 (2008).

    Article  CAS  Google Scholar 

  25. Zhao, J., Sun, B. K., Erwin, J. A., Song, J. J. & Lee, J. T. Polycomb proteins targeted by a short repeat RNA to the mouse X chromosome. Science 322, 750–756 (2008).

    Article  CAS  Google Scholar 

  26. Ogawa, Y., Sun, B. K. & Lee, J. T. Intersection of the RNA interference and X-inactivation pathways. Science 320, 1336–1341 (2008).

    Article  CAS  Google Scholar 

  27. Ashe, H. L., Monks, J., Wijgerde, M., Fraser, P. & Proudfoot, N. J. Intergenic transcription and transinduction of the human β-globin locus. Genes Dev. 11, 2494–2509 (1997).

    Article  CAS  Google Scholar 

  28. Guenther, M. G., Levine, S. S., Boyer, L. A., Jaenisch, R. & Young, R. A. A chromatin landmark and transcription initiation at most promoters in human cells. Cell 130, 77–88 (2007).

    Article  CAS  Google Scholar 

  29. Wang, X. et al. Induced ncRNAs allosterically modify RNA-binding proteins in cis to inhibit transcription. Nature 454, 126–130 (2008).

    Article  CAS  Google Scholar 

  30. Feng, J. et al. The Evf-2 noncoding RNA is transcribed from the Dlx-5/6 ultraconserved region and functions as a Dlx-2 transcriptional coactivator. Genes Dev. 20, 1470–1484 (2006).

    Article  CAS  Google Scholar 

  31. Martianov, I., Ramadass, A., Serra Barros, A., Chow, N. & Akoulitchev, A. Repression of the human dihydrofolate reductase gene by a non-coding interfering transcript. Nature 445, 666–670 (2007).

    Article  CAS  Google Scholar 

  32. Ohno, M., Fukagawa, T., Lee, J. S. & Ikemura, T. Triplex-forming DNAs in the human interphase nucleus visualized in situ by polypurine/polypyrimidine DNA probes and antitriplex antibodies. Chromosoma 111, 201–213 (2002).

    Article  CAS  Google Scholar 

  33. Mariner, P. D. et al. Human Alu RNA is a modular transacting repressor of mRNA transcription during heat shock. Mol. Cell 29, 499–509 (2008).

    Article  CAS  Google Scholar 

  34. He, Y., Vogelstein, B., Velculescu, V. E., Papadopoulos, N. & Kinzler, K. W. The antisense transcriptomes of human cells. Science 322, 1855–1857 (2008).

    Article  CAS  Google Scholar 

  35. Beltran, M. et al. A natural antisense transcript regulates Zeb2/Sip1 gene expression during Snail1-induced epithelial–mesenchymal transition. Genes Dev. 22, 756–769 (2008).

    Article  CAS  Google Scholar 

  36. Willingham, A. T. et al. A strategy for probing the function of noncoding RNAs finds a repressor of NFAT. Science 309, 1570–1573 (2005).

    Article  CAS  Google Scholar 

  37. Yu, W. et al. Epigenetic silencing of tumour suppressor gene p15 by its antisense RNA. Nature 451, 202–206 (2008).

    Article  CAS  Google Scholar 

  38. Hindorff, L. A., Junkins, H. A. & Manolio, T. A. A catalog of published genome-wide association studies. National Human Genome Research Institute [online], (2008).

    Google Scholar 

  39. Tufarelli, C. et al. Transcription of antisense RNA leading to gene silencing and methylation as a novel cause of human genetic disease. Nature Genet. 34, 157–165 (2003).

    Article  CAS  Google Scholar 

  40. Shirasawa, S. et al. SNPs in the promoter of a B cell-specific antisense transcript, SAS-ZFAT, determine susceptibility to autoimmune thyroid disease. Hum. Mol. Genet. 13, 2221–2231 (2004).

    Article  CAS  Google Scholar 

  41. Taft, R. J., Pheasant, M. & Mattick, J. S. The relationship between non-protein-coding DNA and eukaryotic complexity. Bioessays 29, 288–299 (2007).

    Article  CAS  Google Scholar 

  42. Kondo, T. et al. Small peptide regulators of actin-based cell morphogenesis encoded by a polycistronic mRNA. Nature Cell Biol. 9, 660–665 (2007).

    Article  CAS  Google Scholar 

  43. Lin, R., Maeda, S., Liu, C., Karin, M. & Edgington, T. S. A large noncoding RNA is a marker for murine hepatocellular carcinomas and a spectrum of human carcinomas. Oncogene 26, 851–858 (2007).

    Article  CAS  Google Scholar 

  44. Dinger, M. E., Pang, K. C., Mercer, T. R. & Mattick, J. S. Differentiating protein-coding and noncoding RNA: challenges and ambiguities. PLoS Comput. Biol. 4, e1000176 (2008).

    Article  Google Scholar 

  45. Chooniedass-Kothari, S. et al. The steroid receptor RNA activator is the first functional RNA encoding a protein. FEBS Lett. 566, 43–47 (2004).

    Article  CAS  Google Scholar 

  46. Candeias, M. M. et al. p53 mRNA controls p53 activity by managing Mdm2 functions. Nature Cell Biol. 10, 1098–1105 (2008).

    Article  CAS  Google Scholar 

  47. Komar, A. A. Silent SNPs: impact on gene function and phenotype. Pharmacogenomics 8, 1075–1080 (2007).

    Article  CAS  Google Scholar 

  48. Carninci, P. et al. Genome-wide analysis of mammalian promoter architecture and evolution. Nature Genet. 38, 626–635 (2006).

    Article  CAS  Google Scholar 

  49. Jenny, A. et al. A translation-independent role of oskar RNA in early Drosophila oogenesis. Development 133, 2827–2833 (2006).

    Article  CAS  Google Scholar 

  50. Rastinejad, F. & Blau, H. M. Genetic complementation reveals a novel regulatory role for 3′ untranslated regions in growth and differentiation. Cell 72, 903–917 (1993).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank P. Amaral and other laboratory colleagues for many discussions related to this article, and the Australian Research Council for financial support. We apologize both to readers and colleagues for references that were omitted owing to editorial constraint.

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Author notes

  1. Tim R. Mercer and Marcel E. Dinger: T.R.M. and M.E.D. contributed equally to this work

Authors and Affiliations

  1. Tim R. Mercer, Marcel E. Dinger and John S. Mattick are at the Australian Research Council Special Research Centre for Functional and Applied Genomics, Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland 4072, Australia.,

    Tim R. Mercer, Marcel E. Dinger & John S. Mattick

Authors
  1. Tim R. Mercer
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  3. John S. Mattick
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Correspondence to John S. Mattick.

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FURTHER INFORMATION

Mattick laboratory web site

CPC (coding potential calculator)

NRED (ncRNA expression database)

RNAdb (RNA database)

Glossary

Adaptive radiation

Evolution of new morphological or functional characteristics in lineages that diversify in response to environmental changes or to enable colonization of new ecological niches.

Epigenetic

Heritable changes in phenotype caused by mechanisms outside of the genomic sequence. Such changes might remain through cell divisions during, for example, cellular differentiation, or they might persist through subsequent generations. Epigenetic changes include chromatin modifications, such as histone acetylation, or chemical alterations to the DNA itself, such as DNA methylation.

Long ncRNA

Transcripts longer than 200 nucleotides that have little or no protein-coding capacity. Long ncRNAs can regulate gene expression through a diversity of mechanisms.

MicroRNA

Single-stranded RNAs of approximately 21–23 nucleotides that regulate gene expression by partial complementary base pairing to specific mRNAs. This annealing inhibits protein translation and can also facilitate degradation of the target mRNA.

Transvection

Apparent cross-talk between alleles on homologous chromosomes, in which complementation is observed between promoter mutations in one allele and structural mutations in the other. Transvection can cause either gene activation or repression.

X chromosome inactivation

A process in which one of the two copies of the X chromosomes in female mammals is inactivated. X inactivation occurs so that females produce the same dosage of gene products from the X chromosome as males.

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Mercer, T., Dinger, M. & Mattick, J. Long non-coding RNAs: insights into functions. Nat Rev Genet 10, 155–159 (2009). https://doi.org/10.1038/nrg2521

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