Molecular function and evolution of long non-coding RNA derived micro-peptides in normal neuronal differentiation

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Long non-coding RNAs (lncRNAs) are >200nt in length and were thought to lack the ability to encode proteins. They are enriched in the nervous system and ~40% of human lncRNAs are specifically expressed in the brain, with precise spatiotemporal expression profiles.The discovery that long non-coding RNAs (lncRNAs) can be translated to produce non-canonical micro-peptides has revealed an unexplored extension to the human proteome. The function of most of these micro-peptides have yet to be determined. Those that are characterised have important roles, particularly in membranes and mitochondria.We have identified a population of novel neuronal micro-peptides translated from lncRNAs, produced during neuronal differentiation. This project will dissect the molecular function of these neuronal micro-peptides, discover additional novel micro-peptides and reveal the evolutionary history of these lncRNA translation events.Novelty & timeliness: There is now robust evidence of translation lncRNA-derived micro-peptides, but molecular mechanisms still remain a mystery for the majority, though many contribute to cellular function. Having identified translation of novel smORFs within lncRNAs, the exciting next steps are to understand the molecular mechanisms by which these micro-peptides contribute to neuronal differentiation. We have also recently identified potential orthologs for 36% of these neuronal micro-peptides in primates. This provides an exciting basis from which to understand the mechanisms by which novel protein coding genes evolve from lncRNAs.