Resetting transcription factor control circuitry toward ground-state pluripotency in human

Cell. 2014 Sep 11;158(6):1254-1269. doi: 10.1016/j.cell.2014.08.029.

Yasuhiro Takashima ¹, Ge Guo ², Remco Loos ³, Jennifer Nichols ⁴, Gabriella Ficz ⁵, Felix Krueger ⁶, David Oxley ⁶, Fatima Santos ⁶, James Clarke ², William Mansfield ², Wolf Reik ⁷, Paul Bertone ⁸, Austin Smith ⁹

Affiliations

1 Wellcome Trust-Medical Research Council Stem Cell Institute, University of Cambridge, Tennis Court Road, Cambridge CB2 1QR, UK; PRESTO, Japan Science and Technology Agency, 4-1-8 Honcho, Kawaguchi, Saitama, 332-0012, Japan.
2 Wellcome Trust-Medical Research Council Stem Cell Institute, University of Cambridge, Tennis Court Road, Cambridge CB2 1QR, UK.
3 Wellcome Trust-Medical Research Council Stem Cell Institute, University of Cambridge, Tennis Court Road, Cambridge CB2 1QR, UK; European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton CB10 1SD, UK.
4 Wellcome Trust-Medical Research Council Stem Cell Institute, University of Cambridge, Tennis Court Road, Cambridge CB2 1QR, UK; Department of Physiology, Development, and Neuroscience, University of Cambridge, Tennis Court Road, Cambridge CB2 3EG, UK.
5 Centre for Haemato-Oncology, Barts Cancer Institute, University of London, Charterhouse Square, London EC1M 6BQ, UK.
6 Babraham Institute, Babraham, CB22 3AT, UK.
7 Babraham Institute, Babraham, CB22 3AT, UK; Centre for Trophoblast Research, University of Cambridge, Tennis Court Road, Cambridge CB2 3EG, UK; Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton CB10 1SA, UK.
8 Wellcome Trust-Medical Research Council Stem Cell Institute, University of Cambridge, Tennis Court Road, Cambridge CB2 1QR, UK; European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton CB10 1SD, UK; Genome Biology and Developmental Biology Units, European Molecular Biology Laboratory, Meyerhofstraβe 1, 69117 Heidelberg, Germany. Electronic address: bertone@ebi.ac.uk.
9 Wellcome Trust-Medical Research Council Stem Cell Institute, University of Cambridge, Tennis Court Road, Cambridge CB2 1QR, UK; Department of Biochemistry, University of Cambridge, Tennis Court Road, Cambridge CB2 1GA, UK. Electronic address: austin.smith@cscr.cam.ac.uk.

PMID: 25215486 DOI: 10.1016/j.cell.2014.08.029

Abstract

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.

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