Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Cis-acting noncoding RNAs: friends and foes

Nature Structural & Molecular Biology volume 19, pages 1068–1075 (2012)Cite this article

Subjects

Abstract

In recent years, the number and types of known functional noncoding RNAs have increased considerably. A subset of both short- and long-sized species are known to be involved in the cis regulation of target genes located at or near the same genomic locus. Their expression is often coordinated with that of neighboring protein-coding genes, and in many cases, related transcripts can influence each other at one step or another during their biogenesis. Here, we review the current literature, summarizing the existing knowledge about mammalian cis-acting RNAs and their impact on physiological and disease states.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Cis-acting ncRNAs are produced from different origins.
Figure 2: Cis-acting ncRNAs can act at different levels in gene expression pathways.
Figure 3: ncRNAs can promote spatial rearrangement of the surrounding chromatin context.

Similar content being viewed by others

References

  1. Kapranov, P., Willingham, A.T. & Gingeras, T.R. Genome-wide transcription and the implications for genomic organization. Nat. Rev. Genet. 8, 413–423 (2007).

    Article  CAS  PubMed  Google Scholar 

  2. Clark, M.B. et al. The reality of pervasive transcription. PLoS Biol 9, e1000625 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. van Bakel, H., Nislow, C., Blencowe, B.J. & Hughes, T.R. Most “dark matter” transcripts are associated with known genes. PLoS Biol. 8, e1000371 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Huarte, M. & Rinn, J.L. Large non-coding RNAs: missing links in cancer? Hum. Mol. Genet. 19, R152–R161 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Wapinski, O. & Chang, H.Y. Long noncoding RNAs and human disease. Trends Cell Biol. 21, 354–361 (2011).

    Article  CAS  PubMed  Google Scholar 

  6. Rodríguez-Campos, A. & Azorin, F. RNA is an integral component of chromatin that contributes to its structural organization. PLoS ONE 2, e1182 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Tufarelli, C. The silence RNA keeps: cis mechanisms of RNA mediated epigenetic silencing in mammals. Phil. Trans. R. Soc. Lond. B 361, 67–79 (2006).

    Article  CAS  Google Scholar 

  8. Morris, K.V. The emerging role of RNA in the regulation of gene transcription in human cells. Semin. Cell Dev. Biol. 22, 351–358 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Magistri, M., Faghihi, M.A., St Laurent, G. III & Wahlestedt, C. Regulation of chromatin structure by long noncoding RNAs: focus on natural antisense transcripts. Trends Genet. 28, 389–396 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Nie, L. et al. Long non-coding RNAs: versatile master regulators of gene expression and crucial players in cancer. Am. J. Transl. Res. 4, 127–150 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. 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  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  13. Barlow, D.P. Genomic imprinting: a mammalian epigenetic discovery model. Annu. Rev. Genet. 45, 379–403 (2011).

    Article  CAS  PubMed  Google Scholar 

  14. Wan, L.B. & Bartolomei, M.S. Regulation of imprinting in clusters: noncoding RNAs versus insulators. Adv. Genet. 61, 207–223 (2008).

    Article  CAS  PubMed  Google Scholar 

  15. Ferguson-Smith, A.C. Genomic imprinting: the emergence of an epigenetic paradigm. Nat. Rev. Genet. 12, 565–575 (2011).

    Article  CAS  PubMed  Google Scholar 

  16. Lee, J.T. Gracefully ageing at 50, X-chromosome inactivation becomes a paradigm for RNA and chromatin control. Nat. Rev. Mol. Cell Biol. 12, 815–826 (2011).

    Article  CAS  PubMed  Google Scholar 

  17. 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  PubMed  Google Scholar 

  18. Han, J., Kim, D. & Morris, K.V. Promoter-associated RNA is required for RNA-directed transcriptional gene silencing in human cells. Proc. Natl. Acad. Sci. USA 104, 12422–12427 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Neil, H. et al. Widespread bidirectional promoters are the major source of cryptic transcripts in yeast. Nature 457, 1038–1042 (2009).

    Article  CAS  PubMed  Google Scholar 

  20. Xu, Z. et al. Bidirectional promoters generate pervasive transcription in yeast. Nature 457, 1033–1037 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Core, L.J., Waterfall, J.J. & Lis, J.T. Nascent RNA sequencing reveals widespread pausing and divergent initiation at human promoters. Science 322, 1845–1848 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Seila, A.C. et al. Divergent transcription from active promoters. Science 322, 1849–1851 (2008). Refs. 21,22 describe the presence of widespread divergent transcription at the promoters of active protein-coding genes.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Flynn, R.A., Almada, A.E., Zamudio, J.R. & Sharp, P.A. Antisense RNA polymerase II divergent transcripts are P-TEFb dependent and substrates for the RNA exosome. Proc. Natl. Acad. Sci. USA 108, 10460–10465 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  24. Kanhere, A. et al. Short RNAs are transcribed from repressed polycomb target genes and interact with polycomb repressive complex-2. Mol. Cell 38, 675–688 (2010). Shows that 50- to 200-nt RNAs are transcribed from the 5′ end of polycomb-repressed genes in primary T cells and embryonic stem cells and suggests that interaction of these RNAs with polycomb complexes causes gene repression in cis.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Santoro, R., Li, J. & Grummt, I. The nucleolar remodeling complex NoRC mediates heterochromatin formation and silencing of ribosomal gene transcription. Nat. Genet. 32, 393–396 (2002).

    Article  CAS  PubMed  Google Scholar 

  27. Zhou, Y., Santoro, R. & Grummt, I. The chromatin remodeling complex NoRC targets HDAC1 to the ribosomal gene promoter and represses RNA polymerase I transcription. EMBO J. 21, 4632–4640 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Santoro, R. & Grummt, I. Molecular mechanisms mediating methylation-dependent silencing of ribosomal gene transcription. Mol. Cell 8, 719–725 (2001).

    Article  CAS  PubMed  Google Scholar 

  29. Zhou, Y. & Grummt, I. The PHD finger/bromodomain of NoRC interacts with acetylated histone H4K16 and is sufficient for rDNA silencing. Curr. Biol. 15, 1434–1438 (2005).

    Article  CAS  PubMed  Google Scholar 

  30. Schmitz, K.M., Mayer, C., Postepska, A. & Grummt, I. Interaction of noncoding RNA with the rDNA promoter mediates recruitment of DNMT3b and silencing of rRNA genes. Genes Dev. 24, 2264–2269 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Ginno, P.A., Lott, P.L., Christensen, H.C., Korf, I. & Chedin, F. R-loop formation is a distinctive characteristic of unmethylated human CpG island promoters. Mol. Cell 45, 814–825 (2012). Shows that the presence of GC asymmetry at TSSs and the formation of R loops with the transcribed RNA prevents methylation on nearby CGIs.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Heintzman, N.D. et al. Distinct and predictive chromatin signatures of transcriptional promoters and enhancers in the human genome. Nat. Genet. 39, 311–318 (2007).

    Article  CAS  PubMed  Google Scholar 

  33. Heintzman, N.D. et al. Histone modifications at human enhancers reflect global cell-type-specific gene expression. Nature 459, 108–112 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Visel, A. et al. ChIP-seq accurately predicts tissue-specific activity of enhancers. Nature 457, 854–858 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Kim, T.K. et al. Widespread transcription at neuronal activity-regulated enhancers. Nature 465, 182–187 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Wang, D. et al. Reprogramming transcription by distinct classes of enhancers functionally defined by eRNA. Nature 474, 390–394 (2011). Shows that androgen receptor–induced gene-expression reprogramming is marked by the production of eRNAs from active enhancer regions.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Ørom, U.A. et al. Long noncoding RNAs with enhancer-like function in human cells. Cell 143, 46–58 (2010). Describes a set of lincRNAs with positive cis -regulatory roles on nearby expression of protein-coding genes.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Barrallo-Gimeno, A. & Nieto, M.A. The Snail genes as inducers of cell movement and survival: implications in development and cancer. Development 132, 3151–3161 (2005).

    Article  CAS  PubMed  Google Scholar 

  39. Kong, S., Bohl, D., Li, C. & Tuan, D. Transcription of the HS2 enhancer toward a cis-linked gene is independent of the orientation, position, and distance of the enhancer relative to the gene. Mol. Cell. Biol. 17, 3955–3965 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Khalil, A.M. et al. Many human large intergenic noncoding RNAs associate with chromatin-modifying complexes and affect gene expression. Proc. Natl. Acad. Sci. USA 106, 11667–11672 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  41. Katayama, S. et al. Antisense transcription in the mammalian transcriptome. Science 309, 1564–1566 (2005).

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  43. Galante, P.A., Vidal, D.O., de Souza, J.E., Camargo, A.A. & de Souza, S.J. Sense-antisense pairs in mammals: functional and evolutionary considerations. Genome Biol. 8, R40 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Mattick, J.S. RNA regulation: a new genetics? Nat. Rev. Genet. 5, 316–323 (2004).

    Article  CAS  PubMed  Google Scholar 

  45. Lavorgna, G. et al. In search of antisense. Trends Biochem. Sci. 29, 88–94 (2004).

    Article  CAS  PubMed  Google Scholar 

  46. Magistri, M., Faghihi, M.A., St Laurent, G. III & Wahlestedt, C. Regulation of chromatin structure by long noncoding RNAs: focus on natural antisense transcripts. Trends Genet. 28, 389–396 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Tufarelli, C., Frischauf, A.M., Hardison, R., Flint, J. & Higgs, D.R. Characterization of a widely expressed gene (LUC7-LIKE; LUC7L) defining the centromeric boundary of the human alpha-globin domain. Genomics 71, 307–314 (2001).

    Article  CAS  PubMed  Google Scholar 

  48. Tufarelli, C. et al. Transcription of antisense RNA leading to gene silencing and methylation as a novel cause of human genetic disease. Nat. Genet. 34, 157–165 (2003). The first in-depth study showing how an aberrantly expressed antisense transcript can cause DNA hypermethylation and silencing of the juxtaposed gene, resulting in human disease.

    Article  CAS  PubMed  Google Scholar 

  49. Bernard, D. et al. CBX7 controls the growth of normal and tumor-derived prostate cells by repressing the Ink4a/Arf locus. Oncogene 24, 5543–5551 (2005).

    Article  CAS  PubMed  Google Scholar 

  50. Gil, J. & Peters, G. Regulation of the INK4b-ARF-INK4a tumour suppressor locus: all for one or one for all. Nat. Rev. Mol. Cell Biol. 7, 667–677 (2006).

    Article  CAS  PubMed  Google Scholar 

  51. Gil, J., Bernard, D., Martinez, D. & Beach, D. Polycomb CBX7 has a unifying role in cellular lifespan. Nat. Cell Biol. 6, 67–72 (2004).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Pasmant, E. et al. Characterization of a germ-line deletion, including the entire INK4/ARF locus, in a melanoma-neural system tumor family: identification of ANRIL, an antisense noncoding RNA whose expression coclusters with ARF. Cancer Res. 67, 3963–3969 (2007).

    Article  CAS  PubMed  Google Scholar 

  54. Yap, K.L. et al. Molecular interplay of the noncoding RNA ANRIL and methylated histone H3 lysine 27 by polycomb CBX7 in transcriptional silencing of INK4a. Mol. Cell 38, 662–674 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Kotake, Y. et al. Long non-coding RNA ANRIL is required for the PRC2 recruitment to and silencing of p15 (INK4B) tumor suppressor gene. Oncogene 30, 1956–1962 (2011).

    Article  CAS  PubMed  Google Scholar 

  56. Bishop, D.T. et al. Genome-wide association study identifies three loci associated with melanoma risk. Nat. Genet. 41, 920–925 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Pasmant, E. et al. Role of noncoding RNA ANRIL in genesis of plexiform neurofibromas in neurofibromatosis type 1. J. Natl. Cancer Inst. 103, 1713–1722 (2011).

    Article  CAS  PubMed  Google Scholar 

  58. Cunnington, M.S., Santibanez Koref, M., Mayosi, B.M., Burn, J. & Keavney, B. Chromosome 9p21 SNPs associated with multiple disease phenotypes correlate with ANRIL expression. PLoS Genet. 6, e1000899 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. 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  CAS  PubMed  PubMed Central  Google Scholar 

  60. Sopher, B.L. et al. CTCF regulates ataxin-7 expression through promotion of a convergently transcribed, antisense noncoding RNA. Neuron 70, 1071–1084 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Modarresi, F. et al. Inhibition of natural antisense transcripts in vivo results in gene-specific transcriptional upregulation. Nat. Biotechnol. 30, 453–459 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Mondal, T., Rasmussen, M., Pandey, G.K., Isaksson, A. & Kanduri, C. Characterization of the RNA content of chromatin. Genome Res. 20, 899–907 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Krystal, G.W., Armstrong, B.C. & Battey, J.F. N-myc mRNA forms an RNA-RNA duplex with endogenous antisense transcripts. Mol. Cell. Biol. 10, 4180–4191 (1990).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Hastings, M.L., Milcarek, C., Martincic, K., Peterson, M.L. & Munroe, S.H. Expression of the thyroid hormone receptor gene, erbAalpha, in B lymphocytes: alternative mRNA processing is independent of differentiation but correlates with antisense RNA levels. Nucleic Acids Res. 25, 4296–4300 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Yan, M.D. et al. Identification and characterization of a novel gene Saf transcribed from the opposite strand of Fas. Hum. Mol. Genet. 14, 1465–1474 (2005).

    Article  CAS  PubMed  Google Scholar 

  66. Annilo, T., Kepp, K. & Laan, M. Natural antisense transcript of natriuretic peptide precursor A (NPPA): structural organization and modulation of NPPA expression. BMC Mol. Biol. 10, 81 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Alló, M. et al. Control of alternative splicing through siRNA-mediated transcriptional gene silencing. Nat. Struct. Mol. Biol. 16, 717–724 (2009).

    Article  CAS  PubMed  Google Scholar 

  68. Morrissy, A.S., Griffith, M. & Marra, M.A. Extensive relationship between antisense transcription and alternative splicing in the human genome. Genome Res. 21, 1203–1212 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. 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). One of the better-studied cases in which an antisense transcript interferes with processing by splicing of the sense protein-coding gene.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Faghihi, M.A. et al. Expression of a noncoding RNA is elevated in Alzheimer's disease and drives rapid feed-forward regulation of beta-secretase. Nat. Med. 14, 723–730 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Faghihi, M.A. et al. Evidence for natural antisense transcript-mediated inhibition of microRNA function. Genome Biol. 11, R56 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Su, W.Y. et al. Bidirectional regulation between WDR83 and its natural antisense transcript DHPS in gastric cancer. Cell Res. 10.1038/cr.2012.57 (2012).

  73. Dermitzakis, E.T., Reymond, A. & Antonarakis, S.E. Conserved non-genic sequences—an unexpected feature of mammalian genomes. Nat. Rev. Genet. 6, 151–157 (2005).

    Article  CAS  PubMed  Google Scholar 

  74. Louro, R., El-Jundi, T., Nakaya, H.I., Reis, E.M. & Verjovski-Almeida, S. Conserved tissue expression signatures of intronic noncoding RNAs transcribed from human and mouse loci. Genomics 92, 18–25 (2008).

    Article  CAS  PubMed  Google Scholar 

  75. Nakaya, H.I. et al. Genome mapping and expression analyses of human intronic noncoding RNAs reveal tissue-specific patterns and enrichment in genes related to regulation of transcription. Genome Biol. 8, R43 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Valen, E. et al. Biogenic mechanisms and utilization of small RNAs derived from human protein-coding genes. Nat. Struct. Mol. Biol. 18, 1075–1082 (2011).

    Article  CAS  PubMed  Google Scholar 

  77. Guil, S. et al. Intronic RNAs mediate EZH2 regulation of epigenetic targets. Nat. Struct. Mol. Biol. 19, 664–670 (2012).

    Article  CAS  PubMed  Google Scholar 

  78. Horn, P.J. & Peterson, C.L. Molecular biology. Chromatin higher order folding–wrapping up transcription. Science 297, 1824–1827 (2002).

    Article  CAS  PubMed  Google Scholar 

  79. Sexton, T., Schober, H., Fraser, P. & Gasser, S.M. Gene regulation through nuclear organization. Nat. Struct. Mol. Biol. 14, 1049–1055 (2007).

    Article  CAS  PubMed  Google Scholar 

  80. Lanctôt, C., Cheutin, T., Cremer, M., Cavalli, G. & Cremer, T. Dynamic genome architecture in the nuclear space: regulation of gene expression in three dimensions. Nat. Rev. Genet. 8, 104–115 (2007).

    Article  CAS  PubMed  Google Scholar 

  81. Dekker, J. Gene regulation in the third dimension. Science 319, 1793–1794 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Yang, L. et al. ncRNA- and Pc2 methylation-dependent gene relocation between nuclear structures mediates gene activation programs. Cell 147, 773–788 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Kagey, M.H. et al. Mediator and cohesin connect gene expression and chromatin structure. Nature 467, 430–435 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Hadjur, S. et al. Cohesins form chromosomal cis-interactions at the developmentally regulated IFNG locus. Nature 460, 410–413 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Nativio, R. et al. Cohesin is required for higher-order chromatin conformation at the imprinted IGF2–H19 locus. PLoS Genet. 5, e1000739 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Wang, K.C. et al. A long noncoding RNA maintains active chromatin to coordinate homeotic gene expression. Nature 472, 120–124 (2011). Shows how chromosomal looping and lncRNA expression from the 5′ end of the HOXA cluster activates transcription of 5′ end HOXA genes.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Bertani, S., Sauer, S., Bolotin, E. & Sauer, F. The noncoding RNA Mistral activates Hoxa6 and Hoxa7 expression and stem cell differentiation by recruiting MLL1 to chromatin. Mol. Cell 43, 1040–1046 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Cabianca, D.S. et al. A long ncRNA links copy number variation to a polycomb/trithorax epigenetic switch in FSHD muscular dystrophy. Cell 149, 819–831 (2012). In this paper, genetic deletion of a repetitive region causes expression of a lncRNA that acts in cis by interacting with chromatin remodeling factors to de-repress several disease-associated genes.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. van Overveld, P.G. et al. Hypomethylation of D4Z4 in 4q-linked and non-4q-linked facioscapulohumeral muscular dystrophy. Nat. Genet. 35, 315–317 (2003).

    Article  CAS  PubMed  Google Scholar 

  90. Jiang, G. et al. Testing the position-effect variegation hypothesis for facioscapulohumeral muscular dystrophy by analysis of histone modification and gene expression in subtelomeric 4q. Hum. Mol. Genet. 12, 2909–2921 (2003).

    Article  CAS  PubMed  Google Scholar 

  91. Birney, E. et al. Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project. Nature 447, 799–816 (2007).

    Article  CAS  PubMed  Google Scholar 

  92. Guttman, M. et al. Chromatin signature reveals over a thousand highly conserved large non-coding RNAs in mammals. Nature 458, 223–227 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Cabili, M.N. et al. Integrative annotation of human large intergenic noncoding RNAs reveals global properties and specific subclasses. Genes Dev. 25, 1915–1927 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. 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  PubMed  Google Scholar 

  95. 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  PubMed  PubMed Central  Google Scholar 

  96. Wang, X.Q., Crutchley, J.L. & Dostie, J. Shaping the genome with non-coding RNAs. Curr. Genomics 12, 307–321 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Redis, R.S., Berindan-Neagoe, I., Pop, V.I. & Calin, G.A. Non-coding RNAs as theranostics in human cancers. J. Cell. Biochem. 113, 1451–1459 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. Salta, E. & De Strooper, B. Non-coding RNAs with essential roles in neurodegenerative disorders. Lancet Neurol. 11, 189–200 (2012).

    Article  CAS  PubMed  Google Scholar 

  99. Gupta, R.A. et al. Long non-coding RNA HOTAIR reprograms chromatin state to promote cancer metastasis. Nature 464, 1071–1076 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Kino, T. et al. Noncoding RNA gas5 is a growth arrest- and starvation-associated repressor of the glucocorticoid receptor. Sci. Signal. 3, ra8 (2010).

    PubMed  PubMed Central  Google Scholar 

  101. Huarte, M. et al. A large intergenic non-coding RNA induced by p53 mediates global gene repression in the p53 response. Cell 142, 409–419 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Yoon, J.H. et al. LincRNA-p21 suppresses target mRNA translation. Mol. Cell 47, 648–655 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Li, L. et al. Role of human noncoding RNAs in the control of tumorigenesis. Proc. Natl. Acad. Sci. USA 106, 12956–12961 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was supported by the European Research Council under grant agreement no. 268626 EPINORC Advanced grant (M.E.), Ministerio de Ciencia e Innovación (MICINN) grant numbers SAF2011-22895 (S.G.) and SAF2011-22803 (M.E.) and the Health and Science Departments of the Catalan Government (Generalitat de Catalunya). S.G. is funded by the Ramón y Cajal Research Program (MICINN). M.E. is supported as a Catalan Institution for Research and Advanced Studies Research Professor. We apologize to those authors whose work could not be cited here due to space constraints.

Author information

Authors and Affiliations

  1. Cancer Epigenetics and Biology Program, Bellvitge Biomedical Research Institute, L'Hospitalet, Barcelona, Catalonia, Spain

    Sònia Guil & Manel Esteller

  2. Department of Physiological Sciences II, School of Medicine, University of Barcelona, Barcelona, Catalonia, Spain

    Manel Esteller

  3. Institucio Catalana de Recerca i Estudis Avançats, Barcelona, Catalonia, Spain

    Manel Esteller

Authors
  1. Sònia Guil
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Manel Esteller
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Sònia Guil or Manel Esteller.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Guil, S., Esteller, M. Cis-acting noncoding RNAs: friends and foes. Nat Struct Mol Biol 19, 1068–1075 (2012). https://doi.org/10.1038/nsmb.2428

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nsmb.2428

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing