Molecular Criteria for Defining the Naive Human Pluripotent State

Thorold W. Theunissen, Marc Friedli, Yupeng He, Evarist Planet, Ryan C. O'Neil, Styliani Markoulaki, Julien Pontis, Haoyi Wang, Alexandra Iouranova, Michaël Imbeault, Julien Duc, Malkiel A. Cohen, Katherine J. Wert, Rosa Castanon, Zhuzhu Zhang, Yanmei Huang, Joseph R. Nery, Jesse Drotar, Tenzin Lungjangwa, Didier TronoJoseph R. Ecker, Rudolf Jaenisch

Research output: Contribution to journalArticle

150 Scopus citations

Abstract

Recent studies have aimed to convert cultured human pluripotent cells to a naive state, but it remains unclear to what extent the resulting cells recapitulate in vivo naive pluripotency. Here we propose a set of molecular criteria for evaluating the naive human pluripotent state by comparing it to the human embryo. We show that transcription of transposable elements provides a sensitive measure of the concordance between pluripotent stem cells and early human development. We also show that induction of the naive state is accompanied by genome-wide DNA hypomethylation, which is reversible except at imprinted genes, and that the X chromosome status resembles that of the human preimplantation embryo. However, we did not see efficient incorporation of naive human cells into mouse embryos. Overall, the different naive conditions we tested showed varied relationships to human embryonic states based on molecular criteria, providing a backdrop for future analysis of naive human pluripotency.

Original languageEnglish (US)
Pages (from-to)502-515
Number of pages14
JournalCell Stem Cell
Volume19
Issue number4
DOIs
StatePublished - Oct 6 2016
Externally publishedYes

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Keywords

  • DNA methylation
  • embryonic stem cells
  • imprinting
  • mouse-human chimeras
  • pluripotency
  • transposable elements
  • X chromosome reactivation

ASJC Scopus subject areas

  • Molecular Medicine
  • Genetics
  • Cell Biology

Cite this

Theunissen, T. W., Friedli, M., He, Y., Planet, E., O'Neil, R. C., Markoulaki, S., Pontis, J., Wang, H., Iouranova, A., Imbeault, M., Duc, J., Cohen, M. A., Wert, K. J., Castanon, R., Zhang, Z., Huang, Y., Nery, J. R., Drotar, J., Lungjangwa, T., ... Jaenisch, R. (2016). Molecular Criteria for Defining the Naive Human Pluripotent State. Cell Stem Cell, 19(4), 502-515. https://doi.org/10.1016/j.stem.2016.06.011