title: Molecular Criteria for Defining the Naive Human Pluripotent State.
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.
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
authors.forename: Thorold W
authors.initials: TW
authors.lastname: Theunissen
authors.affiliation: School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland.
authors.forename: Marc
authors.initials: M
authors.lastname: Friedli
authors.affiliation: Genomic Analysis Laboratory and Howard Hughes Medical Institute, Salk Institute for Biological Studies, La Jolla, CA 92037, USA; Bioinformatics Program, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Yupeng
authors.initials: Y
authors.lastname: He
authors.affiliation: School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland.
authors.forename: Evarist
authors.initials: E
authors.lastname: Planet
authors.affiliation: Genomic Analysis Laboratory and Howard Hughes Medical Institute, Salk Institute for Biological Studies, La Jolla, CA 92037, USA; Bioinformatics Program, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Ryan C
authors.initials: RC
authors.lastname: O'Neil
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
authors.forename: Styliani
authors.initials: S
authors.lastname: Markoulaki
authors.affiliation: School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland.
authors.forename: Julien
authors.initials: J
authors.lastname: Pontis
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
authors.forename: Haoyi
authors.initials: H
authors.lastname: Wang
authors.affiliation: School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Iouranova
authors.affiliation: School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland.
authors.forename: Michaël
authors.initials: M
authors.lastname: Imbeault
authors.affiliation: School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland.
authors.forename: Julien
authors.initials: J
authors.lastname: Duc
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
authors.forename: Malkiel A
authors.initials: MA
authors.lastname: Cohen
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
authors.forename: Katherine J
authors.initials: KJ
authors.lastname: Wert
authors.affiliation: Genomic Analysis Laboratory and Howard Hughes Medical Institute, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
authors.forename: Rosa
authors.initials: R
authors.lastname: Castanon
authors.affiliation: Genomic Analysis Laboratory and Howard Hughes Medical Institute, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
authors.forename: Zhuzhu
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
authors.forename: Yanmei
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Genomic Analysis Laboratory and Howard Hughes Medical Institute, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Nery
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
authors.forename: Jesse
authors.initials: J
authors.lastname: Drotar
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
authors.forename: Tenzin
authors.initials: T
authors.lastname: Lungjangwa
authors.affiliation: School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland. Electronic address: didier.trono@epfl.ch.
authors.forename: Didier
authors.initials: D
authors.lastname: Trono
authors.affiliation: Genomic Analysis Laboratory and Howard Hughes Medical Institute, Salk Institute for Biological Studies, La Jolla, CA 92037, USA. Electronic address: ecker@salk.edu.
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Ecker
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA. Electronic address: jaenisch@wi.mit.edu.
authors.forename: Rudolf
authors.initials: R
authors.lastname: Jaenisch
mesh_terms: D000818:Animals; D001755:Blastocyst / Q000166:cytology / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics; D002460:Cell Line; D002678:Chimera / Q000378:metabolism; D041321:Chromosomes, Human, X / Q000235:genetics; D002970:Cleavage Stage, Ovum / Q000378:metabolism; D019175:DNA Methylation / Q000235:genetics; D004251:DNA Transposable Elements / Q000235:genetics; D004272:DNA, Mitochondrial / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D015894:Genome, Human; D018392:Genomic Imprinting; D000066449:Human Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D009028:Morula / Q000166:cytology / Q000378:metabolism; D039904:Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D014158:Transcription, Genetic
chemical_list: D004251:DNA Transposable Elements; D004272:DNA, Mitochondrial
keywords: DNA methylation; X chromosome reactivation; embryonic stem cells; imprinting; mouse-human chimeras; pluripotency; transposable elements