LncRNA Meg3 Choreographs the Epigenetic Landscape of Postmitotic Motor Neuron Cell Fate and Subtype Identity

Long-noncoding RNAs (lncRNAs) are numerous and one of their major functions is to regulate transcription via epigenetic regulation. Epigenetic modifications have been shown to have pivotal roles in regulating motor neuron (MN) subtype specification. However, the interplay between long-noncoding RNAs (lncRNAs) and the epigenetic landscape during MN diversification remains unexplored. We systematically identified MN-enriched lncRNAs from embryonic stem cell (ESC)-derived MNs (ESC~MNs) and reveal that lncRNA Meg3 is highly expressed in MNs. Loss of Meg3 leads to ectopic expression of neural progenitor genes and caudal Hox genes. Mechanistically, Meg3 facilitates PRC2/Jarid2 interaction and targets them to non-neuronal genes to maintain postmitotic MN fate, while sculpting MN subtype identity by targeting caudal Hox genes. Absence of lncRNAs (including Meg3) from the Dlk1-Dio3 imprinted locus in embryos leads to ectopic Hoxc8 expression in the Hoxa5 domain and eroded axonal arborization in the proximal nerves of brachial spinal segments. We suggest that Meg3 is a critical lncRNA for choreographing MN cell fate and subtype identity.