AU-rich elements associated with HuR are essential for lncRNAs turnover in murine neuronal stem cells differentiation

Growing number of studies are deeply investigating the functional role that lncRNAs play in gene expression regulation at multiple levels: transcriptional, translational and post-translational processes. Interestingly, a key and essential role for these molecules has been identified in brain development, where genetic ablation of specific lncRNAs (linc-ENC1, linc-BRN1a/b, FABL, TUG1, FENDRR, HOTTIP, PERIL and HAUNT) was shown to cause strong modifications in mouse brain’s development. To this day, it is unknown how these lncRNAs are regulated in the brain and in neural stem cells. Here, we report the identification of a new lncRNA turnover regulatory mechanism involving the binding of the RNA-binding-protein ELAV1/HuR to conserved AU-rich regions present within the sequence of the different lncRNAs under analysis. We suggest that HuR interaction with these lncRNAs plays a regulatory function necessary for the neural stem cells differentiation process, and we demonstrated this by pharmacologic (Di-hydrotanshinone) and genetic (silencing) means. HuR inhibition lead firstly to a modification in the decay rates of the different lncRNAs analyzed, and secondly to a powerful induction of the differentiation process towards their neuronal fate. Moreover, by means of reporter assay we demonstrated that mutations of the AU-rich regions, within the different lncRNA sequences, result in a modification of the molecule’s half-life. In conclusion, we show that lncRNAs turn-over regulation mechanism is similar to the one used by mRNA, involving HuR interaction with AU-rich regions. Moreover, we report that in murine neural stem cells the inhibition of HuR interaction with the lncRNAs analyzed leads to neural differentiation.