The RNA-binding protein Unr prevents mouse embryonic stem cells differentiation toward the primitive endoderm lineage

The maintenance of embryonic stem cells (ESCs) pluripotency depends on key transcription factors, chromatin remodeling proteins, and microRNAs. The roles of RNA-binding proteins are however poorly understood. We report that the cytoplasmic RNA-binding protein Unr prevents the differentiation of ESCs into primitive endoderm (PrE). We show that unr knockout (unr(-/-) ) ESCs spontaneously differentiate into PrE, and that Unr re-expression in unr(-/-) ESCs reverses this phenotype. Nevertheless, unr(-/-) ESCs retain pluripotency, producing differentiated teratomas, and the differentiated unr(-/-) ESCs coexpress the PrE inducer Gata6 and the pluripotency factors Oct4, Nanog, and Sox2. Interestingly, in the differentiated unr(-/-) ESCs, Nanog and Sox2 exhibit a dual nuclear and cytoplasmic localization. This situation, that has never been reported, likely reflects an early differentiation state toward PrE. Finally, we show that Unr destabilizes Gata6 mRNAs and we propose that the post-transcriptional repression of Gata6 expression by Unr contributes to the stabilization of the ESCs pluripotent state.