CyCoNP lncRNA establishes cis and trans RNA-RNA interactions to supervise neuron physiology (CyCoNP RNA Pulldown).

The combination of morphogenetic and transcription factors together with the sinergic aid of noncoding RNAs and their cognate RNA binding proteins (RBP) contribute to shape MN identity. Here, we extend the noncoding perspective of human MN, by detailing the molecular and biological activity of CyCoNP (as Cytoplasmic Coordinator of Neural Progenitors) a highly expressed and MN-enriched human lncRNA. Through RNA purification and loss of function experiments followed by RNA-sequencing, we found that CyCoNP sustains a specific neuron differentiation program, required for the physiology of both neuroblastoma cells and hiPSC-derived MN, mainly by establishing RNA-RNA interactions with the mRNA of NCAM1, a key player in neurogenesis involved in many steps of Central Nervous System development. Specifically, we were able to dissect a dual RNA-mediated mechanism according to which CyCoNP can bind to and sequester, in a stoichiometry-permissive manner, a microRNA that targets pro-neuronal genes included NCAM1 on which the lncRNA play an additional local “in cis” regulation by a direct RNA-RNA interaction. These data highlight novel circuitries involved in the control of human neuron physiology and point out as RNA molecules and the complex relationships they can establish may represent the building blocks of sophisticated cellular mechanisms.