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Cell Rep. 2016 Feb 9;14(5):1181-1194. doi: 10.1016/j.celrep.2015.12.101. Epub 2016 Jan 28.

Nac1 Coordinates a Sub-network of Pluripotency Factors to Regulate Embryonic Stem Cell Differentiation.

Author information

1
Department of Systems Biology, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115, USA. Electronic address: mohan_malleshaiah@hms.harvard.edu.
2
Biostatistics and Computational Biology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA.
3
Department of Genetics, University of Cambridge, Downing Street, Cambridge CB2 3EH, UK.
4
Department of Systems Biology, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115, USA. Electronic address: jeremy_gunawardena@hms.harvard.edu.

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.

PMID:
26832399
PMCID:
PMC4749452
DOI:
10.1016/j.celrep.2015.12.101
[Indexed for MEDLINE]
Free PMC Article

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