Resetting transcription factor control circuitry toward ground-state pluripotency in human.
Elsevier (Cell Press)
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Takashima, Y., Guo, G., Loos, R., Nichols, J., Ficz, G., Krueger, F., Oxley, D., et al. (2014). Resetting transcription factor control circuitry toward ground-state pluripotency in human.. Cell, 158 (6), 1254-1269. https://doi.org/10.1016/j.cell.2014.08.029
Current human pluripotent stem cells lack the transcription factor circuitry that governs the ground state of mouse embryonic stem cells (ESC). Here, we report that short-term expression of two components, NANOG and KLF2, is sufficient to ignite other elements of the network and reset the human pluripotent state. Inhibition of ERK and protein kinase C sustains a transgene-independent rewired state. Reset cells self-renew continuously without ERK signaling, are phenotypically stable, and are karyotypically intact. They differentiate in vitro and form teratomas in vivo. Metabolism is reprogrammed with activation of mitochondrial respiration as in ESC. DNA methylation is dramatically reduced and transcriptome state is globally realigned across multiple cell lines. Depletion of ground-state transcription factors, TFCP2L1 or KLF4, has marginal impact on conventional human pluripotent stem cells but collapses the reset state. These findings demonstrate feasibility of installing and propagating functional control circuitry for ground-state pluripotency in human cells.
Mitochondria, Pluripotent Stem Cells, Animals, Humans, Mice, Homeodomain Proteins, Transcription Factors, Cytological Techniques, Epigenesis, Genetic, Kruppel-Like Transcription Factors, Embryonic Stem Cells, Transcriptome, Nanog Homeobox Protein
This research was supported by the UK Medical Research Council, the Japan Science and Technology agency (JST, PRESTO), the Genome Biology Unit of the European Molecular Biology Laboratory, European Commission projects PluriMes, BetaCellTherapy, EpiGeneSys, and Blueprint, and the Wellcome Trust. Y.T. was a University of Cambridge Herchel Smith Fellow. A.S. is a Medical Research Council Professor.
Japan Science and Technology Agency (JST) (unknown)
External DOI: https://doi.org/10.1016/j.cell.2014.08.029
This record's URL: https://www.repository.cam.ac.uk/handle/1810/286042
Attribution 4.0 International
Licence URL: https://creativecommons.org/licenses/by/4.0/