RT Journal Article
SR Electronic
T1 A common molecular logic determines embryonic stem cell self-renewal and reprogramming
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 200501
DO 10.1101/200501
A1 Sara-Jane Dunn
A1 Meng Amy Li
A1 Elena Carbognin
A1 Austin Smith
A1 Graziano Martello
YR 2018
UL http://biorxiv.org/content/early/2018/06/04/200501.abstract
AB During differentiation and reprogramming new cell identities are generated by reconfiguration of gene regulatory networks. Here we combined automated formal reasoning with experimentation to expose the logic of network activation during induction of naïve pluripotency. We find that a Boolean network architecture defined for maintenance of naïve state embryonic stem cells (ESC) also explains transcription factor behaviour and potency during resetting from primed pluripotency. Computationally identified gene activation trajectories were experimentally substantiated at single cell resolution. Contingency of factor availability explains the counterintuitive observation that Klf2, which is dispensable for ESC maintenance, is required during resetting. We tested 136 predictions formulated by the dynamic network, finding a predictive accuracy of 78.7%. Finally, we show that this network explains and predicts experimental observations of somatic cell reprogramming. We conclude that a common deterministic program of gene regulation is sufficient to govern maintenance and induction of naïve pluripotency. The tools exemplified here could be broadly applied to delineate dynamic networks underlying cell fate transitions.