RMSS 2017

Sara-Jane Dunn

Naïve pluripotency is the capacity of embryonic stem cells to differentiate into all cell lineages of the adult body. For many years, this property was unique to these cells alone, but just over a decade ago, scientists demonstrated the capacity to induce the pluripotent state from somatic cells. This requires the forced expression of select transcription factors, which form part of an interaction network that safeguards the naïve state. Unfortunately, this process is inefficient, pivotal genetic interactions are uncertain, and the sequence of molecular events is poorly delineated. We combined automated formal reasoning with experimentation to expose the logic of network reprogramming for induction of naïve pluripotency. In so doing, we derived a biological program that accurately predicted the reprogramming potency of single factors, as well as pairs of factors that dramatically accelerate the process, enabling dissection of the network trajectory at single cell resolution. Moreover, this program recapitulates the dynamics of conversion, and yielded counterintuitive observations for the requirement of specific factors. We conclude that installation of naïve pluripotency is an ordered process, highly dependent on the presence of specific network components. Moreover, we propose that this methodology could be applied widely for the study of development and direct lineage reprogramming.