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:

The multilayered complexity of ceRNA crosstalk and competition

Abstract

Recent reports have described an intricate interplay among diverse RNA species, including protein-coding messenger RNAs and non-coding RNAs such as long non-coding RNAs, pseudogenes and circular RNAs. These RNA transcripts act as competing endogenous RNAs (ceRNAs) or natural microRNA sponges — they communicate with and co-regulate each other by competing for binding to shared microRNAs, a family of small non-coding RNAs that are important post-transcriptional regulators of gene expression. Understanding this novel RNA crosstalk will lead to significant insight into gene regulatory networks and have implications in human development and disease.

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

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

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

Figure 1: PTEN competing endogenous RNA (ceRNA) network.
Figure 2: Variable factors that may influence competing endogenous RNA (ceRNA) effectiveness.

Similar content being viewed by others

References

  1. Volders, P. J. et al. LNCipedia: a database for annotated human lncRNA transcript sequences and structures. Nucleic Acids Res. 41, D246–D251 (2013).

    Article  CAS  PubMed  Google Scholar 

  2. Dunham, I. et al. An integrated encyclopedia of DNA elements in the human genome. Nature 489, 57–74 (2012).

    Article  ADS  CAS  Google Scholar 

  3. Nagano, T. & Fraser, P. No-nonsense functions for long noncoding RNAs. Cell 145, 178–181 (2011).

    CAS  PubMed  Google Scholar 

  4. Brockdorff, N. et al. The product of the mouse Xist gene is a 15 kb inactive X-specific transcript containing no conserved ORF and located in the nucleus. Cell 71, 515–526 (1992).

    Article  CAS  PubMed  Google Scholar 

  5. Shabalina, S. A. & Spiridonov, N. A. The mammalian transcriptome and the function of non-coding DNA sequences. Genome Biol. 5, 105 (2004).

    Article  PubMed  PubMed Central  Google Scholar 

  6. Gutschner, T. & Diederichs, S. The hallmarks of cancer: a long non-coding RNA point of view. RNA Biol. 9, 703–719 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Mattick, J. S. Non-coding RNAs: the architects of eukaryotic complexity. EMBO Rep. 2, 986–991 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. 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  PubMed  Google Scholar 

  9. Guttman, M. & Rinn, J. L. Modular regulatory principles of large non-coding RNAs. Nature 482, 339–346 (2012).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  10. Ebert, M. S. & Sharp, P. A. Emerging roles for natural microRNA sponges. Curr. Biol. 20, R858–R861 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Salmena, L. et al. A ceRNA hypothesis: the Rosetta Stone of a hidden RNA language? Cell 146, 353–358 (2011). This essay proposes that all types of RNA transcripts may crosstalk and be co-regulated through a predictable 'ceRNA language' of RNA, and summarizes the experimental evidence in support of the ceRNA hypothesis at the time.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Seitz, H. Redefining microRNA targets. Curr. Biol. 19, 870–873 (2009).

    Article  CAS  PubMed  Google Scholar 

  13. Wee, L. M., Flores-Jasso, C. F., Salomon, W. E. & Zamore, P. D. Argonaute divides its RNA guide into domains with distinct functions and RNA-binding properties. Cell 151, 1055–1067 (2012). This work investigates the effect of miRNA and sponge transcript abundance on the efficacy of miRNA target repression and proposes that the ceRNA hypothesis may only apply to a subset of moderate or low abundance miRNAs.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Cazalla, D., Yario, T. & Steitz, J. A. Down-regulation of a host microRNA by a Herpesvirus saimiri noncoding RNA. Science 328, 1563–1566 (2010). This work extends ceRNA crosstalk to viruses and shows that a viral non-coding RNA sequesters and promotes the degradation of a miRNA in infected host cells.

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  15. Franco-Zorrilla, J. M. et al. Target mimicry provides a new mechanism for regulation of microRNA activity. Nature Genet. 39, 1033–1037 (2007). This study in plants, which demonstrates effective sequestration of miR-399 by the non-coding transcript IPS1, was the first to describe a role for non-coding RNAs as natural microRNA sponges in eukaryotic cells.

    Article  CAS  PubMed  Google Scholar 

  16. Poliseno, L. et al. A coding-independent function of gene and pseudogene mRNAs regulates tumour biology. Nature 465, 1033–1038 (2010). This work focusing on the PTEN pseudogene was the first to define a functional role for expressed pseudogenes in cancer as well as attribute a ceRNA function to pseudogene and protein-coding mRNAs.

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  17. Tay, Y. et al. Coding-independent regulation of the tumor suppressor PTEN by competing endogenous mRNAs. Cell 147, 344–357 (2011). This study presents a combined computational and experimental approach that can be used as a framework to predict and validate ceRNA interactions.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Karreth, F. A. et al. In vivo identification of tumor-suppressive PTEN ceRNAs in an oncogenic BRAF-induced mouse model of melanoma. Cell 147, 382–395 (2011). This work used a Sleeping Beauty insertional mutagenesis screen to identify and validate ceRNAs in vivo.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Sanchez-Diaz, P. & Penalva, L. O. Post-transcription meets post-genomic: the saga of RNA binding proteins in a new era. RNA Biol. 3, 101–109 (2006).

    Article  CAS  PubMed  Google Scholar 

  20. Lal, A. et al. Concurrent versus individual binding of HuR and AUF1 to common labile target mRNAs. EMBO J. 23, 3092–3102 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Barker, A. et al. Sequence requirements for RNA binding by HuR and AUF1. J. Biochem. 151, 423–437 (2012).

    Article  CAS  PubMed  Google Scholar 

  22. Al-Ahmadi, W. et al. Alternative polyadenylation variants of the RNA binding protein, HuR: abundance, role of AU-rich elements and auto-regulation. Nucleic Acids Res. 37, 3612–3624 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Yoo, S. et al. A HuD-ZBP1 ribonucleoprotein complex localizes GAP-43 mRNA into axons through its 3′ untranslated region AU-rich regulatory element. J. Neurochem. 126, 792–804 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Cesana, M. et al. A long noncoding RNA controls muscle differentiation by functioning as a competing endogenous RNA. Cell 147, 358–369 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Wang, J. et al. CREB up-regulates long non-coding RNA, HULC expression through interaction with microRNA-372 in liver cancer. Nucleic Acids Res. 38, 5366–5383 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Sumazin, P. et al. An extensive microRNA-mediated network of RNA-RNA interactions regulates established oncogenic pathways in glioblastoma. Cell 147, 370–381 (2011). This work in glioblastoma demonstrates that ceRNA interactions between approximately 7,000 transcripts are part of a surprisingly extensive post-transcriptional regulatory layer.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Lee, D. Y. et al. A 3′-untranslated region (3′UTR) induces organ adhesion by regulating miR-199a* functions. PLoS ONE 4, e4527 (2009).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  28. Brown, B. D. et al. Endogenous microRNA can be broadly exploited to regulate transgene expression according to tissue, lineage and differentiation state. Nature Biotechnol. 25, 1457–1467 (2007).

    Article  CAS  Google Scholar 

  29. Carè, A. et al. MicroRNA-133 controls cardiac hypertrophy. Nature Med. 13, 613–618 (2007).

    Article  CAS  PubMed  Google Scholar 

  30. Ebert, M. S., Neilson, J. R. & Sharp, P. A. MicroRNA sponges: competitive inhibitors of small RNAs in mammalian cells. Nature Methods 4, 721–726 (2007). This study is the first to describe the use of an experimental miRNA sponge to inhibit miRNA function.

    Article  CAS  PubMed  Google Scholar 

  31. Ebert, M. S. & Sharp, P. A. MicroRNA sponges: progress and possibilities. RNA 16, 2043–2050 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Kluiver, J. et al. Generation of miRNA sponge constructs. Methods 58, 113–117 (2012).

    Article  CAS  PubMed  Google Scholar 

  33. Gentner, B. et al. Stable knockdown of microRNA in vivo by lentiviral vectors. Nature Methods 6, 63–66 (2009).

    Article  CAS  PubMed  Google Scholar 

  34. Valastyan, S. et al. A pleiotropically acting microRNA, miR-31, inhibits breast cancer metastasis. Cell 137, 1032–1046 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Brown, B. D. & Naldini, L. Exploiting and antagonizing microRNA regulation for therapeutic and experimental applications. Nature Rev. Genet. 10, 578–585 (2009).

    Article  CAS  PubMed  Google Scholar 

  36. Haraguchi, T., Ozaki, Y. & Iba, H. Vectors expressing efficient RNA decoys achieve the long-term suppression of specific microRNA activity in mammalian cells. Nucleic Acids Res. 37, e43 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Johnsson, P. et al. A pseudogene long-noncoding-RNA network regulates PTEN transcription and translation in human cells. Nature Struct. Mol. Biol. 20, 440–446 (2013).

    Article  CAS  Google Scholar 

  38. Mitrovich, Q. M. & Anderson, P. mRNA surveillance of expressed pseudogenes in C. elegans. Curr. Biol. 15, 963–967 (2005).

    Article  CAS  PubMed  Google Scholar 

  39. Marques, A. C. et al. Evidence for conserved post-transcriptional roles of unitary pseudogenes and for frequent bifunctionality of mRNAs. Genome Biol. 13, R102 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Fan, M. et al. A long non-coding RNA, PTCSC3, as a tumor suppressor and a target of miRNAs in thyroid cancer cells. Exp. Ther. Med. 5, 1143–1146 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Kallen, A. N. et al. The imprinted H19 lncRNA antagonizes Let-7 microRNAs. Mol. Cell 52, 101–112 (2013).

    Article  CAS  PubMed  Google Scholar 

  43. Wang, Y. et al. Endogenous miRNA sponge lincRNA-RoR regulates Oct4, Nanog, and Sox2 in human embryonic stem cell self-renewal. Dev. Cell 25, 69–80 (2013).

    Article  CAS  PubMed  Google Scholar 

  44. Capel, B. et al. Circular transcripts of the testis-determining gene Sry in adult mouse testis. Cell 73, 1019–1030 (1993).

    Article  CAS  PubMed  Google Scholar 

  45. Hansen, T. B. et al. Natural RNA circles function as efficient microRNA sponges. Nature 495, 384–388 (2013). This study was one of the first to functionalize circRNAs as a new class of highly stable and efficient natural miRNA ceRNAs.

    Article  ADS  CAS  PubMed  Google Scholar 

  46. Memczak, S. et al. Circular RNAs are a large class of animal RNAs with regulatory potency. Nature 495, 333–338 (2013).

    Article  ADS  CAS  PubMed  Google Scholar 

  47. Jeck, W. R. et al. Circular RNAs are abundant, conserved, and associated with ALU repeats. RNA 19, 141–157 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Taulli, R., Loretelli, C. & Pandolfi, P. P. From pseudo-ceRNAs to circ-ceRNAs: a tale of cross-talk and competition. Nature Struct. Mol. Biol. 20, 541–543 (2013).

    Article  CAS  Google Scholar 

  49. Wilusz, J. E. & Sharp, P. A. Molecular biology. A circuitous route to noncoding RNA. Science 340, 440–441 (2013).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  50. Lee, D. Y. et al. Expression of versican 3′-untranslated region modulates endogenous microRNA functions. PLoS ONE 5, e13599 (2010).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  51. Fang, L. et al. Versican 3′-untranslated region (3′-UTR) functions as a ceRNA in inducing the development of hepatocellular carcinoma by regulating miRNA activity. FASEB J. 27, 907–919 (2013).

    Article  CAS  PubMed  Google Scholar 

  52. Jeyapalan, Z. et al. Expression of CD44 3′-untranslated region regulates endogenous microRNA functions in tumorigenesis and angiogenesis. Nucleic Acids Res. 39, 3026–3041 (2011).

    Article  CAS  PubMed  Google Scholar 

  53. Rutnam, Z. J. & Yang, B. B. The non-coding 3′ UTR of CD44 induces metastasis by regulating extracellular matrix functions. J. Cell Sci. 125, 2075–2085 (2012).

    Article  CAS  PubMed  Google Scholar 

  54. Kumar, M. S. et al. Hmga2 functions as a competing endogenous RNA to promote lung cancer progression. Nature http://dx.doi.org/10.1038/nature12785 (2013). This study was the first to demonstrate that an abundant mRNA protein-coding transcript can act as ceRNA to out compete an abundant miRNA such as Let7.

  55. Libri, V. et al. Murine cytomegalovirus encodes a miR-27 inhibitor disguised as a target. Proc. Natl Acad. Sci. USA 109, 279–284 (2012).

    Article  ADS  PubMed  Google Scholar 

  56. Marcinowski, L. et al. Degradation of cellular mir-27 by a novel, highly abundant viral transcript is important for efficient virus replication in vivo. PLoS Pathog. 8, e1002510 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Thomas, M., Lieberman, J. & Lal, A. Desperately seeking microRNA targets. Nature Struct. Mol. Biol. 17, 1169–1174 (2010).

    Article  CAS  Google Scholar 

  58. Sarver, A. L. & Subramanian, S. Competing endogenous RNA database. Bioinformation 8, 731–733 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  59. Chi, S. W., Zang, J. B., Mele, A. & Darnell, R. B. Argonaute HITS-CLIP decodes microRNA-mRNA interaction maps. Nature 460, 479–486 (2009).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  60. Hafner, M. et al. Transcriptome-wide identification of RNA-binding protein and microRNA target sites by PAR-CLIP. Cell 141, 129–141 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Thomson, D. W., Bracken, C. P. & Goodall, G. J. Experimental strategies for microRNA target identification. Nucleic Acids Res. 39, 6845–6853 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Schug, J. et al. Dynamic recruitment of microRNAs to their mRNA targets in the regenerating liver. BMC Genomics 14, 264 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Yoon, J. H., Srikantan, S. & Gorospe, M. MS2-TRAP (MS2-tagged RNA affinity purification): tagging RNA to identify associated miRNAs. Methods 58, 81–87 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Mukherji, S. et al. MicroRNAs can generate thresholds in target gene expression. Nature Genet. 43, 854–859 (2011).

    Article  CAS  PubMed  Google Scholar 

  65. Ala, U. et al. Integrated transcriptional and competitive endogenous RNA networks are cross-regulated in permissive molecular environments. Proc. Natl Acad. Sci. USA 110, 7154–7159 (2013).

    Article  ADS  MathSciNet  PubMed  PubMed Central  Google Scholar 

  66. Figliuzzi, M., Marinari, E. & De Martino, A. MicroRNAs as a selective channel of communication between competing RNAs: a steady-state theory. Biophys. J. 104, 1203–1213 (2013).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  67. Loinger, A. et al. Competition between small RNAs: a quantitative view. Biophys. J. 102, 1712–1721 (2012).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  68. Srikantan, S., Tominaga, K. & Gorospe, M. Functional interplay between RNA-binding protein HuR and microRNAs. Curr. Protein Pept. Sci. 13, 372–379 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Bhattacharyya, S. N. et al. Relief of microRNA-mediated translational repression in human cells subjected to stress. Cell 125, 1111–1124 (2006).

    Article  CAS  PubMed  Google Scholar 

  70. Srikantan, S. et al. Translational control of TOP2A influences doxorubicin efficacy. Mol. Cell. Biol. 31, 3790–3801 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Tominaga, K. et al. Competitive regulation of nucleolin expression by HuR and miR-494. Mol. Cell. Biol. 31, 4219–4231 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Young, L. E. et al. The mRNA stability factor HuR inhibits microRNA-16 targeting of COX-2. Mol. Cancer Res. 10, 167–180 (2012).

    Article  CAS  PubMed  Google Scholar 

  73. Epis, M. R. et al. The RNA-binding protein HuR opposes the repression of ERBB-2 gene expression by microRNA miR-331–3p in prostate cancer cells. J. Biol. Chem. 286, 41442–41454 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Kim, H. H. et al. HuR recruits let-7/RISC to repress c-Myc expression. Genes Dev. 23, 1743–1748 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Glorian, V. et al. HuR-dependent loading of miRNA RISC to the mRNA encoding the Ras-related small GTPase RhoB controls its translation during UV-induced apoptosis. Cell Death Differ. 18, 1692–1701 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Kedde, M. et al. RNA-binding protein Dnd1 inhibits microRNA access to target mRNA. Cell 131, 1273–1286 (2007).

    Article  CAS  PubMed  Google Scholar 

  77. Ma, F. et al. MicroRNA-466l upregulates IL-10 expression in TLR-triggered macrophages by antagonizing RNA-binding protein tristetraprolin-mediated IL-10 mRNA degradation. J. Immunol. 184, 6053–6059 (2010).

    Article  CAS  PubMed  Google Scholar 

  78. Nishikura, K. Editor meets silencer: crosstalk between RNA editing and RNA interference. Nature Rev. Mol. Cell Biol. 7, 919–931 (2006).

    Article  CAS  Google Scholar 

  79. Maas, S. Posttranscriptional recoding by RNA editing. Adv. Protein Chem. Struct. Biol. 86, 193–224 (2012).

    Article  CAS  PubMed  Google Scholar 

  80. Kawahara, Y. et al. Redirection of silencing targets by adenosine-to-inosine editing of miRNAs. Science 315, 1137–1140 (2007).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  81. Kawahara, Y. et al. Frequency and fate of microRNA editing in human brain. Nucleic Acids Res. 36, 5270–5280 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Athanasiadis, A., Rich, A. & Maas, S. Widespread A-to-I RNA editing of Alu-containing mRNAs in the human transcriptome. PLoS Biol. 2, e391 (2004).

    Article  PubMed  PubMed Central  Google Scholar 

  83. Levanon, E. Y. et al. Systematic identification of abundant A-to-I editing sites in the human transcriptome. Nature Biotechnol. 22, 1001–1005 (2004).

    Article  CAS  Google Scholar 

  84. Song, M. S., Salmena, L. & Pandolfi, P. P. The functions and regulation of the PTEN tumour suppressor. Nature Rev. Mol. Cell Biol. 13, 283–296 (2012).

    Article  CAS  Google Scholar 

  85. Panzitt, K. et al. Characterization of HULC, a novel gene with striking up-regulation in hepatocellular carcinoma, as noncoding RNA. Gastroenterology 132, 330–342 (2007).

    Article  CAS  PubMed  Google Scholar 

  86. Mayr, C. & Bartel, D. P. Widespread shortening of 3′UTRs by alternative cleavage and polyadenylation activates oncogenes in cancer cells. Cell 138, 673–684 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Lembo, A., Di Cunto, F. & Provero, P. Shortening of 3′UTRs correlates with poor prognosis in breast and lung cancer. PLoS ONE 7, e31129 (2012).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  88. Pal, S., Gupta, R. & Davuluri, R. V. Alternative transcription and alternative splicing in cancer. Pharmacol. Ther. 136, 283–294 (2012).

    Article  CAS  PubMed  Google Scholar 

  89. Venables, J. P. et al. Cancer-associated regulation of alternative splicing. Nature Struct. Mol. Biol. 16, 670–676 (2009).

    Article  CAS  Google Scholar 

  90. Mallick, B. & Ghosh, Z. A complex crosstalk between polymorphic microRNA target sites and AD prognosis. RNA Biol. 8, 665–673 (2011).

    Article  CAS  PubMed  Google Scholar 

  91. Almeida, M. I., Reis, R. M. & Calin, G. A. Decoy activity through microRNAs: the therapeutic implications. Expert Opin. Biol. Ther. 12, 1153–1159 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Tollervey, D. Molecular biology: RNA lost in translation. Nature 440, 425–426 (2006).

    Article  ADS  CAS  PubMed  Google Scholar 

  93. Mercer, T. R. et al. Expression of distinct RNAs from 3′ untranslated regions. Nucleic Acids Res. 39, 2393–2403 (2011).

    Article  ADS  CAS  PubMed  Google Scholar 

  94. Khorshid, M., Hausser, J., Zavolan, M. & van Nimwegen, E. A biophysical miRNA-mRNA interaction model infers canonical and noncanonical targets. Nature Methods 10, 253–255 (2013).

    Article  CAS  PubMed  Google Scholar 

  95. Helwak, A., Kudla, G., Dudnakova, T. & Tollervey, D. Mapping the human miRNA interactome by CLASH reveals frequent noncanonical binding. Cell 153, 654–665 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Tay, Y. et al. MicroRNAs to Nanog, Oct4 and Sox2 coding regions modulate embryonic stem cell differentiation. Nature 455, 1124–1128 (2008).

    Article  ADS  CAS  PubMed  Google Scholar 

  97. Hausser, J., Syed, A. P., Bilen, B. & Zavolan, M. Analysis of CDS-located miRNA target sites suggests that they can effectively inhibit translation. Genome Res. 23, 604–615 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Vasudevan, S., Tong, Y. & Steitz, J. A. Switching from repression to activation: microRNAs can up-regulate translation. Science 318, 1931–1934 (2007).

    Article  ADS  CAS  PubMed  Google Scholar 

  99. Meijer, H. A. et al. Translational repression and eIF4A2 activity are critical for microRNA-mediated gene regulation. Science 340, 82–85 (2013).

    Article  ADS  CAS  PubMed  Google Scholar 

  100. Ibarra-Laclette, E. et al. Architecture and evolution of a minute plant genome. Nature 498, 94–98 (2013).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank S. M. Tan, R. Taulli, F. Karreth and other members of the Pandolfi laboratory for helpful discussions and critical review of the manuscript. Y.T. received a Special Fellow Award from The Leukemia & Lymphoma Society. P.P.P. was supported by US National Institutes of Health grant R01 CA-82328.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Pier Paolo Pandolfi.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Additional information

Reprints and permissions information is available at www.nature.com/reprints.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Tay, Y., Rinn, J. & Pandolfi, P. The multilayered complexity of ceRNA crosstalk and competition. Nature 505, 344–352 (2014). https://doi.org/10.1038/nature12986

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature12986

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

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