A common molecular logic determines embryonic stem cell self-renewal and reprogramming.
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Dunn, S., Li, M. A., Carbognin, E., Smith, A., & Martello, G. (2019). A common molecular logic determines embryonic stem cell self-renewal and reprogramming.. EMBO J, 38 (1) https://doi.org/10.15252/embj.2018100003
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 by RT-qPCR Contingency of factor availability explains the counterintuitive observation that Klf2, which is dispensable for ESC maintenance, is required during resetting. We tested 124 predictions formulated by the dynamic network, finding a predictive accuracy of 77.4%. 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.
abstract boolean network, formal verification, maintenance and reprogramming, naive pluripotency, transcription factor network modelling, Animals, CRISPR-Cas Systems, Cell Differentiation, Cell Self Renewal, Cells, Cultured, Cellular Reprogramming, Computational Biology, Embryonic Stem Cells, Epigenesis, Genetic, Gene Expression Profiling, Gene Expression Regulation, Developmental, Gene Regulatory Networks, Mice, Mouse Embryonic Stem Cells, Pluripotent Stem Cells
S-J.D. is supported by Microsoft Research. G.M.’s laboratory is supported by grants from Giovanni Armenise-Harvard Foundation and Telethon Foundation (TCP13013). A.S. and M.A.L. are funded by the BBSRC. The Cambridge Stem Cell Institute receives core funding from the Wellcome Trust and Medical Research Council. M.A.L. was a Sir Henry Wellcome Postdoctoral fellow and received support from the University of Cambridge Institutional Strategic Support Fund. AS is a Medical Research Council professor.
Wellcome Trust (204845/Z/16/Z)
Biotechnology and Biological Sciences Research Council (BB/P021573/1)
External DOI: https://doi.org/10.15252/embj.2018100003
This record's URL: https://www.repository.cam.ac.uk/handle/1810/286704
Attribution 4.0 International
Licence URL: https://creativecommons.org/licenses/by/4.0/
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