The expression of long non-coding RNAs is highly enriched in the human nervous system. However, the function of neuronal lncRNAs in the cytoplasm and their potential translation remains poorly understood. Here we performed Poly-Ribo-Seq to understand the interaction of lncRNAs with the translation machinery and the functional consequences during neuronal differentiation of human SH-SH5Y cells. We discovered 237 cytoplasmic lncRNAs upregulated during early neuronal differentiation, 58-70% of which are associated with polysome translation complexes. Amongst these polysome associated lncRNAs, we find 45 small ORFs to be actively translated, 17 specifically upon differentiation. 15/45 of the translated lncRNA-smORFs exhibit sequence conservation within Hominidea suggesting they are under strong selective constraint in this clade. Profiling of publicly available datasets revealed that 8/45 of the translated lncRNAs are dynamically expressed during human brain development and 22/45 are associated with cancers of the central nervous system. One translated lncRNA we discovered is LINC01116, which is induced upon differentiation and contains an 87 codon smORF exhibiting increased ribosome profiling signal upon differentiation. The resulting LINC01116 peptide localises to neurites. Knockdown of LINC01116 results in a significant reduction of neurite length in differentiated cells indicating it contributes to neuronal differentiation. Our findings indicate cytoplasmic lncRNAs interact with translation complexes, are a non-canonical source of novel peptides, and contribute to neuronal function and disease. Specifically, we demonstrate a novel functional role for LINC01116 during human neuronal differentiation.
CORE (COnnecting REpositories)
CORE (COnnecting REpositories)