Distinct Molecular Trajectories Converge to Induce Naive Pluripotency.

Abstract

To decipher how cellular identity is instructed by interplay between transcription factors and signals, we employ defined reprogramming systems in which genetic and signalling parameters can be independently varied and successfully transitioning cells isolated. We show that naïve pluripotency can be induced from EpiSCs along transcriptionally and mechanistically distinct routes. Relative to development, one route moves forward, with productive cells acquiring mesodermal signature prior to naïve pluripotency induction. In contrast, another route overshoots backwards, transcriptionally resembling the earlier embryo and gaining its greater developmental potency. Nevertheless, these distinct trajectories reach the same endpoint, demonstrating surprising flexibility for the establishment of a single identity from a single origin. We reconcile route differences, revealing precise Oct4 expression as a unifying, essential and sufficient feature. We propose that fine-tuned regulation of this ‘transition factor’ underpins multidimensional access to the naïve identity. This offers a conceptual framework for the understanding of cell identity transitions.