MicroRNA miR-124 controls the choice between neuronal and astrocyte differentiation by fine-tuning Ezh2 expression [Gene Regulation]

May 30th, 2014 by Neo, W. H., Yap, K., Lee, S. H., Looi, L. S., Khandelia, P., Neo, S. X., V.Makeyev, E., Su, I.-h.

Polycomb group protein Ezh2 is a H3K27 histone methyltransferase orchestrating an extensive epigenetic regulatory program. Several nervous system (NS)-specific genes are known to be repressed by Ezh2 in stem cells and de-repressed during neuronal differentiation. However, molecular mechanisms underlying this regulation remain poorly understood. Here we show that Ezh2 levels are dampened during neuronal differentiation by brain-enriched microRNA miR-124. Expression of miR-124 in a neuroblastoma cells line was sufficient to up-regulate a significant fraction of NS-specific Ezh2 target genes. On the other hand, naturally elevated expression of miR-124 in embryonic carcinoma cells undergoing neuronal differentiation correlated with down-regulation of Ezh2 levels. Importantly, over-expression of Ezh2 mRNA with 3′ untranslated region (3′UTR) lacking functional miR-124 binding site, but not with the wild-type Ezh2 3′UTR, hampered neuronal and promoted astrocyte-specific differentiation in P19 and embryonic mouse neural stem cells. Overall, our results uncover a molecular mechanism that allows miR-124 to balance the choice between alternative differentiation possibilities through fine-tuning the expression of a critical epigenetic regulator.