title: Network plasticity of pluripotency transcription factors in embryonic stem cells.
abstract: Transcription factor (TF) networks are thought to regulate embryonic stem cell (ESC) pluripotency. However, TF expression dynamics and regulatory mechanisms are poorly understood. We use reporter mouse ESC lines allowing non-invasive quantification of Nanog or Oct4 protein levels and continuous long-term single-cell tracking and quantification over many generations to reveal diverse TF protein expression dynamics. For cells with low Nanog expression, we identified two distinct colony types: one re-expressed Nanog in a mosaic pattern, and the other did not re-express Nanog over many generations. Although both expressed pluripotency markers, they exhibited differences in their TF protein correlation networks and differentiation propensities. Sister cell analysis revealed that differences in Nanog levels are not necessarily accompanied by differences in the expression of other pluripotency factors. Thus, regulatory interactions of pluripotency TFs are less stringently implemented in individual self-renewing ESCs than assumed at present.
authors.affiliation: Research Unit Stem Cell Dynamics, Helmholtz Zentrum München-German Research Center for Environmental Health, Ingolstädter Landstr. 1, 85764 Neuherberg, Germany.
authors.forename: Adam
authors.initials: A
authors.lastname: Filipczyk
authors.affiliation: Institute of Computational Biology, Helmholtz Zentrum München-German Research Center for Environmental Health, Ingolstädter Landstr. 1, 85764 Neuherberg, Germany.
authors.forename: Carsten
authors.initials: C
authors.lastname: Marr
authors.affiliation: Research Unit Stem Cell Dynamics, Helmholtz Zentrum München-German Research Center for Environmental Health, Ingolstädter Landstr. 1, 85764 Neuherberg, Germany.|Department of Biosystems Science and Engineering, ETH Zurich, 4058 Basel, Switzerland.
authors.forename: Simon
authors.initials: S
authors.lastname: Hastreiter
authors.affiliation: Institute of Computational Biology, Helmholtz Zentrum München-German Research Center for Environmental Health, Ingolstädter Landstr. 1, 85764 Neuherberg, Germany.
authors.forename: Justin
authors.initials: J
authors.lastname: Feigelman
authors.affiliation: Institute of Computational Biology, Helmholtz Zentrum München-German Research Center for Environmental Health, Ingolstädter Landstr. 1, 85764 Neuherberg, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Schwarzfischer
authors.affiliation: Research Unit Stem Cell Dynamics, Helmholtz Zentrum München-German Research Center for Environmental Health, Ingolstädter Landstr. 1, 85764 Neuherberg, Germany.|Department of Biosystems Science and Engineering, ETH Zurich, 4058 Basel, Switzerland.
authors.forename: Philipp S
authors.initials: PS
authors.lastname: Hoppe
authors.affiliation: Research Unit Stem Cell Dynamics, Helmholtz Zentrum München-German Research Center for Environmental Health, Ingolstädter Landstr. 1, 85764 Neuherberg, Germany.|Department of Biosystems Science and Engineering, ETH Zurich, 4058 Basel, Switzerland.
authors.forename: Dirk
authors.initials: D
authors.lastname: Loeffler
authors.affiliation: Research Unit Stem Cell Dynamics, Helmholtz Zentrum München-German Research Center for Environmental Health, Ingolstädter Landstr. 1, 85764 Neuherberg, Germany.|Department of Biosystems Science and Engineering, ETH Zurich, 4058 Basel, Switzerland.
authors.forename: Konstantinos D
authors.initials: KD
authors.lastname: Kokkaliaris
authors.affiliation: Research Unit Stem Cell Dynamics, Helmholtz Zentrum München-German Research Center for Environmental Health, Ingolstädter Landstr. 1, 85764 Neuherberg, Germany.|Department of Biosystems Science and Engineering, ETH Zurich, 4058 Basel, Switzerland.
authors.forename: Max
authors.initials: M
authors.lastname: Endele
authors.affiliation: Research Unit Stem Cell Dynamics, Helmholtz Zentrum München-German Research Center for Environmental Health, Ingolstädter Landstr. 1, 85764 Neuherberg, Germany.|Institute of Computational Biology, Helmholtz Zentrum München-German Research Center for Environmental Health, Ingolstädter Landstr. 1, 85764 Neuherberg, Germany.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Schauberger
authors.affiliation: Research Unit Stem Cell Dynamics, Helmholtz Zentrum München-German Research Center for Environmental Health, Ingolstädter Landstr. 1, 85764 Neuherberg, Germany.|Institute of Computational Biology, Helmholtz Zentrum München-German Research Center for Environmental Health, Ingolstädter Landstr. 1, 85764 Neuherberg, Germany.|Department of Biosystems Science and Engineering, ETH Zurich, 4058 Basel, Switzerland.
authors.forename: Oliver
authors.initials: O
authors.lastname: Hilsenbeck
authors.affiliation: Research Unit Stem Cell Dynamics, Helmholtz Zentrum München-German Research Center for Environmental Health, Ingolstädter Landstr. 1, 85764 Neuherberg, Germany.|Department of Biosystems Science and Engineering, ETH Zurich, 4058 Basel, Switzerland.
authors.forename: Stavroula
authors.initials: S
authors.lastname: Skylaki
authors.affiliation: Institute of Computational Biology, Helmholtz Zentrum München-German Research Center for Environmental Health, Ingolstädter Landstr. 1, 85764 Neuherberg, Germany.|Technische Universität München, Center for Mathematics, Chair of Mathematical Modelling of Biological Systems, Boltzmannstraße 3, 85748 Garching, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Hasenauer
authors.affiliation: Stem Cell Engineering, Biotechnology Center, Technische Universität Dresden, 01307 Dresden, Germany.
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Anastassiadis
authors.affiliation: Institute of Computational Biology, Helmholtz Zentrum München-German Research Center for Environmental Health, Ingolstädter Landstr. 1, 85764 Neuherberg, Germany.|Technische Universität München, Center for Mathematics, Chair of Mathematical Modelling of Biological Systems, Boltzmannstraße 3, 85748 Garching, Germany.
authors.forename: Fabian J
authors.initials: FJ
authors.lastname: Theis
authors.affiliation: Research Unit Stem Cell Dynamics, Helmholtz Zentrum München-German Research Center for Environmental Health, Ingolstädter Landstr. 1, 85764 Neuherberg, Germany.|Department of Biosystems Science and Engineering, ETH Zurich, 4058 Basel, Switzerland.
authors.forename: Timm
authors.initials: T
authors.lastname: Schroeder
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics; D058948:Cell Tracking / Q000379:methods; D002478:Cells, Cultured; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism*; D015870:Gene Expression; D053263:Gene Regulatory Networks; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008856:Microscopy, Fluorescence; D000071317:Nanog Homeobox Protein; D050814:Octamer Transcription Factor-3 / Q000235:genetics / Q000378:metabolism; D039904:Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D059010:Single-Cell Analysis / Q000379:methods; D059008:Time-Lapse Imaging / Q000379:methods; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014161:Transduction, Genetic; D000097573:Red Fluorescent Protein
chemical_list: D001426:Bacterial Proteins; D049452:Green Fluorescent Proteins; D018398:Homeodomain Proteins; D008164:Luminescent Proteins; D000071317:Nanog Homeobox Protein; D050814:Octamer Transcription Factor-3; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors; D000097573:Red Fluorescent Protein; C475540:Nanog protein, mouse; C054562:yellow fluorescent protein, Bacteria