A common molecular logic determines embryonic stem cell self-renewal and reprogramming

Reconfiguration of gene regulatory networks is required to instate new cell identities during differentiation and reprogramming. Here we combined automated formal reasoning with experimentation to expose the logic of network resetting for induction of naive pluripotency. We found that a Boolean network architecture defined for self-renewal accurately predicted reprogramming potency of single or combinations of factors. Deterministic gene activation trajectories were computationally identified and experimentally substantiated at single cell resolution. A counterintuitive observation that Klf2 is required during resetting while dispensable for self-renewal is explained by the contingency of factor availability. We tested 132 predictions formulated by the dynamic network, finding a predictive accuracy of 79.6%, and further show that this network accurately explains experimental observations of somatic cell reprogramming. We conclude that a common and deterministic program of gene regulation governs both self-renewal and induction of pluripotency. The methodology could be applied to delineate dynamic networks underlying other cell fate transitions.