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 Trono; Joseph R. Ecker; Rudolf Jaenisch

doi:10.1016/j.stem.2016.06.011

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 Trono^*Joseph R. Ecker, Rudolf Jaenisch

^*Corresponding author for this work

Cell & Developmental Biology

Research output: Contribution to journal › Article › peer-review

380 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 language	English (US)
Pages (from-to)	502-515
Number of pages	14
Journal	Cell stem cell
Volume	19
Issue number	4
DOIs	https://doi.org/10.1016/j.stem.2016.06.011
State	Published - Oct 6 2016

Funding

We thank Ruth Flannery for embryo processing, Patti Wisniewski and Colin Zollo for cell sorting, the University of Lausanne Genomic core facility for sequencing, and Dr. Jacob Hanna (Weizmann Institute) for sharing cells. This study was supported by grants from the Simons Foundation (SFLIFE #286977 to R.J.) and in part by the NIH (RO1-CA084198) to R.J., and from the Swiss National Science Foundation and the European Research Council (KRABnKAP, No. 268721) to D.T. The work in the J.R.E. laboratory was supported by the Howard Hughes Medical Institute and Gordon and Betty Moore Foundation (GBMF3034) and the Mary K. Chapman Foundation. J.R.E. is an Investigator of the Howard Hughes Medical Institute. T.W.T. is supported by a Sir Henry Wellcome Postdoctoral Fellowship (098889/Z/12/Z), J.P. by a Foundation Bettencourt Award and by the Association pour la Recherche sur le Cancer (ARC), and M.I. by a postdoctoral training grant from the Fonds de la Recherche en Sant\u00E9 du Qu\u00E9bec. R.J. is co-founder of Fate Therapeutics and an adviser to Stemgent.

Keywords

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

ASJC Scopus subject areas

Molecular Medicine
Genetics
Cell Biology

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10.1016/j.stem.2016.06.011

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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

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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.",

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year = "2016",

month = oct,

day = "6",

doi = "10.1016/j.stem.2016.06.011",

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Theunissen, TW, Friedli, M, He, Y, Planet, E, O'Neil, RC, Markoulaki, S, Pontis, J, Wang, H, Iouranova, A, Imbeault, M, Duc, J, Cohen, MA, Wert, KJ, Castanon, R, Zhang, Z, Huang, Y, Nery, JR, Drotar, J, Lungjangwa, T, Trono, D, Ecker, JR & Jaenisch, R 2016, 'Molecular Criteria for Defining the Naive Human Pluripotent State', Cell stem cell, vol. 19, no. 4, pp. 502-515. https://doi.org/10.1016/j.stem.2016.06.011

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AU - Theunissen, Thorold W.

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AU - He, Yupeng

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AU - Markoulaki, Styliani

AU - Pontis, Julien

AU - Wang, Haoyi

AU - Iouranova, Alexandra

AU - Imbeault, Michaël

AU - Duc, Julien

AU - Cohen, Malkiel A.

AU - Wert, Katherine J.

AU - Castanon, Rosa

AU - Zhang, Zhuzhu

AU - Huang, Yanmei

AU - Nery, Joseph R.

AU - Drotar, Jesse

AU - Lungjangwa, Tenzin

AU - Trono, Didier

AU - Ecker, Joseph R.

AU - Jaenisch, Rudolf

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N2 - 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.

AB - 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.

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KW - X chromosome reactivation

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ER -

Molecular Criteria for Defining the Naive Human Pluripotent State

Abstract

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Keywords

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