Distinct Molecular Trajectories Converge to Induce Naive Pluripotency.
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Authors
Lohoff, Tim
Bates, Lawrence E
Lim, Chee Y
Sousa, Elsa J
Maskalenka, Katsiaryna
Radzisheuskaya, Aliaksandra
Lloyd, Rebecca L
Nestorowa, Sonia
Humphreys, Peter
Mansfield, William
Reik, Wolf
Publication Date
2019-09Journal Title
Cell stem cell
ISSN
1934-5909
Publisher
Cell Press
Volume
25
Issue
3
Pages
388-406.e8
Language
eng
Type
Article
This Version
AM
Physical Medium
Print-Electronic
Metadata
Show full item recordCitation
Stuart, H. T., Stirparo, G., Lohoff, T., Bates, L. E., Kinoshita, M., Lim, C. Y., Sousa, E. J., et al. (2019). Distinct Molecular Trajectories Converge to Induce Naive Pluripotency.. Cell stem cell, 25 (3), 388-406.e8. https://doi.org/10.1016/j.stem.2019.07.009
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.
Sponsorship
HTS is
funded by MRC PhD Studentship 1233706, JCRS by Wellcome Fellowship WT101861, and BG by Bloodwise, CRUK, Wellcome and NIH-NIDDK. The authors gratefully acknowledge core support from the Wellcome-MRC Cambridge Stem Cell Institute.
Funder references
Wellcome Trust (101861/Z/13/Z)
Wellcome Trust (097922/Z/11/Z)
WELLCOME TRUST (105031/D/14/Z)
MRC (MR/R017735/1)
MRC (MC_PC_12009)
BBSRC (BB/M004023/1)
BBSRC (BB/P009867/1)
BBSRC (BB/R018588/1)
Identifiers
External DOI: https://doi.org/10.1016/j.stem.2019.07.009
This record's URL: https://www.repository.cam.ac.uk/handle/1810/293215
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