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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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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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