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

Abstract

Summary: 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. : Progenitor cells choose a distinct fate between alternative choices during development. Malleshaiah et al. now show that pluripotent mouse embryonic stem cells decide between mesendodermal and neuroectodermal fates through a sub-network of pluripotency transcription factors, Oct4, Sox2, Tcf3, and Nac1, that is coordinated by Nac1 and constrains protein levels within distinct ranges in each fate.