title: Nac1 Coordinates a Sub-network of Pluripotency Factors to Regulate Embryonic Stem Cell Differentiation.
abstract: Pluripotent cells give rise to distinct cell types during development and are regulated by often self-reinforcing molecular networks. How such networks allow cells to differentiate is less well understood. Here, we use integrative methods to show that external signals induce reorganization of the mouse embryonic stem cell pluripotency network and that a sub-network of four factors, Nac1, Oct4, Tcf3, and Sox2, regulates their differentiation into the alternative mesendodermal and neuroectodermal fates. In the mesendodermal fate, Nac1 and Oct4 were constrained within quantitative windows, whereas Sox2 and Tcf3 were repressed. In contrast, in the neuroectodermal fate, Sox2 and Tcf3 were constrained while Nac1 and Oct4 were repressed. In addition, we show that Nac1 coordinates differentiation by activating Oct4 and inhibiting both Sox2 and Tcf3. Reorganization of progenitor cell networks around shared factors might be a common differentiation strategy and our integrative approach provides a general methodology for delineating such networks.
authors.affiliation: Department of Systems Biology, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115, USA. Electronic address: mohan_malleshaiah@hms.harvard.edu.
authors.forename: Mohan
authors.initials: M
authors.lastname: Malleshaiah
authors.affiliation: Biostatistics and Computational Biology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA.
authors.forename: Megha
authors.initials: M
authors.lastname: Padi
authors.affiliation: Department of Genetics, University of Cambridge, Downing Street, Cambridge CB2 3EH, UK.
authors.forename: Pau
authors.initials: P
authors.lastname: Rué
authors.affiliation: Biostatistics and Computational Biology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA.
authors.forename: John
authors.initials: J
authors.lastname: Quackenbush
authors.affiliation: Department of Genetics, University of Cambridge, Downing Street, Cambridge CB2 3EH, UK.
authors.forename: Alfonso
authors.initials: A
authors.lastname: Martinez-Arias
authors.affiliation: Department of Systems Biology, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115, USA. Electronic address: jeremy_gunawardena@hms.harvard.edu.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Gunawardena
mesh_terms: D000818:Animals; D001483:Base Sequence; D002454:Cell Differentiation / Q000235:genetics; D019070:Cell Lineage / Q000235:genetics; D019295:Computational Biology; D008648:Mesoderm / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D000066450:Mouse Embryonic Stem Cells / Q000166:cytology* / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D054258:Neural Plate / Q000378:metabolism; D050814:Octamer Transcription Factor-3 / Q000378:metabolism; D039904:Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism*; D011485:Protein Binding / Q000235:genetics; D012045:Regulatory Sequences, Nucleic Acid / Q000235:genetics; D012097:Repressor Proteins / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism
chemical_list: C484605:Nacc1 protein, mouse; D009419:Nerve Tissue Proteins; D050814:Octamer Transcription Factor-3; D012097:Repressor Proteins; D014157:Transcription Factors
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