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Long non-coding antisense RNA controls Uchl1 translation through an embedded SINEB2 repeat

Abstract

Most of the mammalian genome is transcribed1,2,3. This generates a vast repertoire of transcripts that includes protein-coding messenger RNAs, long non-coding RNAs (lncRNAs) and repetitive sequences, such as SINEs (short interspersed nuclear elements). A large percentage of ncRNAs are nuclear-enriched with unknown function4. Antisense lncRNAs may form sense–antisense pairs by pairing with a protein-coding gene on the opposite strand to regulate epigenetic silencing, transcription and mRNA stability5,6,7,8,9,10. Here we identify a nuclear-enriched lncRNA antisense to mouse ubiquitin carboxy-terminal hydrolase L1 (Uchl1), a gene involved in brain function and neurodegenerative diseases11. Antisense Uchl1 increases UCHL1 protein synthesis at a post-transcriptional level, hereby identifying a new functional class of lncRNAs. Antisense Uchl1 activity depends on the presence of a 5′ overlapping sequence and an embedded inverted SINEB2 element. These features are shared by other natural antisense transcripts and can confer regulatory activity to an artificial antisense to green fluorescent protein. Antisense Uchl1 function is under the control of stress signalling pathways, as mTORC1 inhibition by rapamycin causes an increase in UCHL1 protein that is associated to the shuttling of antisense Uchl1 RNA from the nucleus to the cytoplasm. Antisense Uchl1 RNA is then required for the association of the overlapping sense protein-coding mRNA to active polysomes for translation. These data reveal another layer of gene expression control at the post-transcriptional level.

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Figure 1: Expression of antisense Uchl1 in dopaminergic neurons.
Figure 2: Antisense Uchl1 regulates UCHL1 protein levels via an embedded inverted SINEB2 element.
Figure 3: Natural and synthetic antisense lncRNAs increase target protein levels.
Figure 4: Antisense Uchl1 mediates UCHL1 protein induction by rapamycin.

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References

  1. 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  ADS  CAS  Google Scholar 

  2. The FANTOM Consortium The transcriptional landscape of the mammalian genome. Science 309, 1559–1563 (2005)

    Article  ADS  Google Scholar 

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

    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  ADS  CAS  Google Scholar 

  5. 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 

  6. Ebralidze, A. K. et al. PU.1 expression is modulated by the balance of functional sense and antisense RNAs regulated by a shared cis-regulatory element. Genes Dev. 22, 2085–2092 (2008)

    Article  CAS  Google Scholar 

  7. Hastings, M. L., Ingle, H. A., Lazar, M. A. & Munroe, S. H. Post-transcriptional regulation of thyroid hormone receptor expression by cis-acting sequences and a naturally occurring antisense RNA. J. Biol. Chem. 275, 11507–11513 (2000)

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  ADS  Google Scholar 

  10. Spigoni, G., Gedressi, C. & Mallamaci, A. Regulation of Emx2 expression by antisense transcripts in murine cortico-cerebral precursors. PLoS ONE 5, e8658 (2010)

    Article  ADS  Google Scholar 

  11. Setsuie, R. & Wada, K. The functions of UCH-L1 and its relation to neurodegenerative diseases. Neurochem. Int. 51, 105–111 (2007)

    Article  CAS  Google Scholar 

  12. Liu, Y., Fallon, L., Lashuel, H. A., Liu, Z. & Lansbury, P. T., Jr The UCH-L1 gene encodes two opposing enzymatic activities that affect α-synuclein degradation and Parkinson’s disease susceptibility. Cell 111, 209–218 (2002)

    Article  CAS  Google Scholar 

  13. Barrachina, M. et al. Reduced ubiquitin C-terminal hydrolase-1 expression levels in dementia with Lewy bodies. Neurobiol. Dis. 22, 265–273 (2006)

    Article  CAS  Google Scholar 

  14. Barrachina, M. et al. Amyloid-β deposition in the cerebral cortex in dementia with Lewy bodies is accompanied by a relative increase in AβPP mRNA isoforms containing the Kunitz protease inhibitor. Neurochem. Int. 46, 253–260 (2005)

    Article  CAS  Google Scholar 

  15. Choi, J. et al. Oxidative modifications and down-regulation of ubiquitin carboxyl-terminal hydrolase L1 associated with idiopathic Parkinson’s and Alzheimer’s diseases. J. Biol. Chem. 279, 13256–13264 (2004)

    Article  CAS  Google Scholar 

  16. Nishihara, H., Smit, A. F. & Okada, N. Functional noncoding sequences derived from SINEs in the mammalian genome. Genome Res. 16, 864–874 (2006)

    Article  CAS  Google Scholar 

  17. Ponicsan, S. L., Kugel, J. F. & Goodrich, J. A. Genomic gems: SINE RNAs regulate mRNA production. Curr. Opin. Genet. Dev. 20, 149–155 (2010)

    Article  CAS  Google Scholar 

  18. Quentin, Y. Fusion of a free left Alu monomer and a free right Alu monomer at the origin of the Alu family in the primate genomes. Nucleic Acids Res. 20, 487–493 (1992)

    Article  CAS  Google Scholar 

  19. Andrei, M. A. et al. A role for eIF4E and eIF4E-transporter in targeting mRNPs to mammalian processing bodies. RNA 11, 717–727 (2005)

    Article  CAS  Google Scholar 

  20. Merrick, W. C. Eukaryotic protein synthesis: still a mystery. J. Biol. Chem. 285, 21197–21201 (2010)

    Article  CAS  Google Scholar 

  21. Prasanth, K. V. et al. Regulating gene expression through RNA nuclear retention. Cell 123, 249–263 (2005)

    Article  CAS  Google Scholar 

  22. Holcik, M. & Sonenberg, N. Translational control in stress and apoptosis. Nature Rev. Mol. Cell Biol. 6, 318–327 (2005)

    Article  CAS  Google Scholar 

  23. Gilbert, W. V. Alternative ways to think about cellular internal ribosome entry. J. Biol. Chem. 285, 29033–29038 (2010)

    Article  CAS  Google Scholar 

  24. Yoon, A. et al. Impaired control of IRES-mediated translation in X-linked dyskeratosis congenita. Science 312, 902–906 (2006)

    Article  ADS  CAS  Google Scholar 

  25. Malagelada, C., Jin, Z. H., Jackson-Lewis, V., Przedborski, S. & Greene, L. A. Rapamycin protects against neuron death in in vitro and in vivo models of Parkinson’s disease. J. Neurosci. 30, 1166–1175 (2010)

    Article  CAS  Google Scholar 

  26. Santini, E., Heiman, M., Greengard, P., Valjent, E. & Fisone, G. Inhibition of mTOR signaling in Parkinson’s disease prevents L-DOPA-induced dyskinesia. Sci. Signal. 2, ra36 (2009)

    Article  Google Scholar 

  27. Vandesompele, J. et al. Accurate normalization of real-time quantitative RT-PCR data by geometric averaging of multiple internal control genes. Genome Biol. 3, RESEARCH0034 (2002)

    Article  Google Scholar 

  28. Biagioli, M. et al. Unexpected expression of α- and β-globin in mesencephalic dopaminergic neurons and glial cells. Proc. Natl Acad. Sci. USA 106, 15454–15459 (2009)

    Article  ADS  CAS  Google Scholar 

  29. Ishii, T., Omura, M. & Mombaerts, P. Protocols for two- and three-color fluorescent RNA in situ hybridization of the main and accessory olfactory epithelia in mouse. J. Neurocytol. 33, 657–669 (2004)

    Article  CAS  Google Scholar 

  30. Nordström, K. J. et al. Critical evaluation of the FANTOM3 non-coding RNA transcripts. Genomics 94, 169–176 (2009)

    Article  Google Scholar 

  31. Maglott, D. R., Katz, K. S., Sicotte, H. & Pruitt, K. D. NCBI’s LocusLink and RefSeq. Nucleic Acids Res. 28, 126–128 (2000)

    Article  CAS  Google Scholar 

  32. Kent, W. J. et al. The human genome browser at UCSC. Genome Res. 12, 996–1006 (2002)

    Article  CAS  Google Scholar 

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Acknowledgements

We thank S.G. laboratory members for thought-provoking discussions and C. Leonesi for technical help. We thank F. Persichetti, A. Mallamaci, E. Calautti, S. Saoncella, A. Lunardi, D. De Pietri Tonelli, R. Sanges, M. E. MacDonald and T. Perlmann for support and discussions; and M. J. Zigmond and B. Joseph for sharing the MN9D cell line. This work was supported by the FP7 Dopaminet to S.G., E.S. and P.C., by The Giovanni Armenise-Harvard Foundation to S.G. and by the Compagnia di San Paolo to S.B.

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Contributions

C.C. designed and performed the experiments, and analysed the results; L.Ci. designed and performed the experiments, and analysed the results; M.B. designed and performed the experiments, and analysed the results; A.B. prepared polysomes; S.Z. designed the experiments, analysed the results and wrote the manuscript; S.F. carried out qRT–PCR on polysome fractions and the pulse labelling experiment; E.P. prepared polysomes and carried out northern blotting; I.F. analysed the results; L.Co. designed the experiments and analysed the results; C.S. analysed the data and discussed the results; A.R.R.F. performed bioinformatic analysis for the identification of SINEB2 and family members and designed ΔAlu and ΔSINEB2 mutants; P.C. provided reagents, experimental design and managing; S.B. designed polysome experiments, analysed the data and wrote the manuscript; E.S. performed bioinformatic analysis for the identification of S–AS pairs, designed experiments for the analysis of antisense Uchl1 expression and analysed the results; S.G. designed the experiments, analysed the results and wrote the paper.

Corresponding author

Correspondence to Stefano Gustincich.

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Competing interests

S.G., C.C., S.Z., A.R.R.F. and P.C. have filed for a patent application. S.G., S.Z., C.S. and P.C. declare competing financial interests as co-founders of TransSINE Technologies.

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Carrieri, C., Cimatti, L., Biagioli, M. et al. Long non-coding antisense RNA controls Uchl1 translation through an embedded SINEB2 repeat. Nature 491, 454–457 (2012). https://doi.org/10.1038/nature11508

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