The expression of long noncoding 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-SY5Y cells. We discovered 237 cytoplasmic lncRNAs up-regulated during early neuronal differentiation, 58%–70% of which are associated with polysome translation complexes. Among these polysome-associated lncRNAs, we find 45 small ORFs to be actively translated, 17 specifically upon differentiation. Fifteen of 45 of the translated lncRNA-smORFs exhibit sequence conservation within Hominidea, suggesting they are under strong selective constraint in this clade. The profiling of publicly available data sets 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 localizes 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 noncanonical source of novel peptides, and contribute to neuronal function and disease. Specifically, we demonstrate a novel functional role for LINC01116 during human neuronal differentiation.

中文翻译：

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细胞质长链非编码 RNA 在人类神经元分化过程中受到差异调节和翻译

长链非编码 RNA 的表达在人类神经系统中高度丰富。然而，细胞质中神经元 lncRNA 的功能及其潜在的翻译仍然知之甚少。在这里，我们进行了 Poly-Ribo-Seq，以了解 lncRNA 与翻译机制的相互作用以及人类 SH-SY5Y 细胞神经元分化过程中的功能后果。我们发现 237 个细胞质 lncRNA 在早期神经元分化过程中上调，其中 58%–70% 与多核糖体翻译复合物有关。在这些与多核糖体相关的 lncRNA 中，我们发现 45 个小 ORF 被主动翻译，其中 17 个特别是在分化时。45 个已翻译的 lncRNA-smORF 中有 15 个在 Hominiidea 中表现出序列保守性，表明它们在这个进化枝中受到强烈的选择约束。公开数据集的分析表明，8/45 的翻译 lncRNA 在人类大脑发育过程中动态表达，22/45 与中枢神经系统癌症有关。我们发现的一种翻译的 lncRNA 是LINC01116，它在分化时被诱导并且含有 87 个密码子 smORF，在分化时表现出增加的核糖体分析信号。所得的 LINC01116 肽定位于神经突。击倒LINC01116导致分化细胞中神经突长度的显着减少，表明它有助于神经元分化。我们的研究结果表明，细胞质 lncRNA 与翻译复合物相互作用，是新肽的非规范来源，并有助于神经元功能和疾病。具体来说，我们展示了LINC01116在人类神经元分化过程中的新功能作用。