Journal Article

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

Collavin, Licio, Gustincich, Stefano, Carninci, Piero, Pesce, Elisa, Stupka, Elia, Biffo, Stefano, Fedele, Stefania, Cimatti, Laura, Zucchelli, Silvia, Santoro, Claudio, Forrest, Alistair R. R., Ferrer, Isidre, Biagioli, Marta, Beugnet, Anne, Carrieri, Claudia

2012

Overview

Antisense Uchl1 , a long non-coding RNA that is an antisense transcript for the Uchl1 gene, upregulates UCHL1 protein levels through the combined action of an overlapping sequence at its 5′ end and an embedded SINEB2 element. Antisense long non-coding RNA controls gene expression Many of the RNAs transcribed from the genome have as yet no known function. One such long non-coding RNA (lncRNA) is an antisense transcript for the ubiquitin carboxy-terminal hydrolase L1 ( Uchl1 ) gene, which is involved in brain function and implicated in neurodegeneration. This study shows that the antisense Uchl1 lncRNA recognizes a short interspersed nuclear element, SINEB2, within the Uchl1 gene. Interaction of antisense Uchl1 with SINEB2 results in upregulation of UCHL1 expression at the translational level. Natural or synthetic antisense transcripts with embedded repetitive elements may prove useful as tools to increase translation of selected messenger RNAs, and may have potential as RNA therapeutics. Most of the mammalian genome is transcribed 1 , 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 function 4 . 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 stability 5 , 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 diseases 11 . 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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/337/384/2568 / 631/337/574 / 631/378 / Analytical, structural and metabolic biochemistry / Animals / Anti-Bacterial Agents - pharmacology / Antisense RNA / Biological and medical sciences / Cell Line / Cloning / Enzymes / Fundamental and applied biological sciences. Psychology / Gene expression / Genetic translation / Humanities and Social Sciences / Humans / Hydrolases / Identification and classification / Kinases / letter / Male / Mice / Molecular and cellular biology / multidisciplinary / Neurons / Observations / Physiological aspects / Properties / Protein Biosynthesis - drug effects / Protein Biosynthesis - genetics / Protein synthesis / Proteins / RNA polymerase / RNA, Antisense - genetics / RNA, Antisense - metabolism / Science / Sequence Inversion / Short Interspersed Nucleotide Elements - genetics / Sirolimus - pharmacology / Translation (Genetics) / Ubiquitin Thiolesterase - genetics / Ubiquitin Thiolesterase - metabolism