STAT3-dependent long non-coding RNA Lncenc1 contributes to mouse ES cells pluripotency via stabilizing Klf4 mRNA

Embryonic stem cells (ESCs) preserve the unique ability to differentiate into any somatic cell lineage while maintaining their self-renewal potential, relying on a complex interplay of extracellular signals regulating the expression/activity of pluripotency transcription factors and their targets. Leukemia inhibitory factor (LIF)-activated STAT3 drives ESCs' stemness by a number of mechanisms, including the transcriptional induction of pluripotency factors such as Klf4 and the maintenance of a stem-like epigenetic landscape. However, it is unknown if STAT3 directly controls stem-cell specific non-coding RNAs, crucial to balance pluripotency and differentiation. Applying a bioinformatic pipeline, here we identify Lncenc1 in mouse ESCs as an STAT3-dependent long non-coding RNA that supports pluripotency. Lncenc1 acts in the cytoplasm as a positive feedback regulator of the LIF-STAT3 axis by competing for the binding of microRNA-128 to the 3'UTR of the Klf4 core pluripotency factor mRNA, enhancing its expression. Our results unveil a novel non-coding RNA-based mechanism for LIF-STAT3-mediated pluripotency.