Pluripotency Factors in Embryonic Stem Cells Regulate Differentiation into Germ Layers

FAS Center for Systems Biology, Harvard University, Cambridge, MA 02138, USA.
Cell (Impact Factor: 32.24). 06/2011; 145(6):875-89. DOI: 10.1016/j.cell.2011.05.017
Source: PubMed


Cell fate decisions are fundamental for development, but we do not know how transcriptional networks reorganize during the transition from a pluripotent to a differentiated cell state. Here, we asked how mouse embryonic stem cells (ESCs) leave the pluripotent state and choose between germ layer fates. By analyzing the dynamics of the transcriptional circuit that maintains pluripotency, we found that Oct4 and Sox2, proteins that maintain ESC identity, also orchestrate germ layer fate selection. Oct4 suppresses neural ectodermal differentiation and promotes mesendodermal differentiation; Sox2 inhibits mesendodermal differentiation and promotes neural ectodermal differentiation. Differentiation signals continuously and asymmetrically modulate Oct4 and Sox2 protein levels, altering their binding pattern in the genome, and leading to cell fate choice. The same factors that maintain pluripotency thus also integrate external signals and control lineage selection. Our study provides a framework for understanding how complex transcription factor networks control cell fate decisions in progenitor cells.

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    • "A growing body of evidence underscores the importance of pluripotency factors during differentiation. Human and mouse ES cell studies have demonstrated that the core pluripotency transcription factors, SOX2, OCT4, and NANOG, play distinct roles in coordinating ES cell lineage commitment (Lu et al., 2009; Thomson et al., 2011; Wang et al., 2012). NANOG promotes definitive endoderm (DE) formation by coordinating with the activation of the TGF-b signaling pathway through the induction of EOMES (Teo et al., 2011). "
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    ABSTRACT: We demonstrate that the pluripotency gene OCT4 has a role in regulating differentiation via Wnt signaling. OCT4 expression levels in human embryonic stem cells increases transiently during the first 24 hr of in vitro differentiation, with OCT4 occupancy increasing at endoderm regulators such as SOX17 and FOXA2. This increased occupancy correlates with loss of the PRC2 complex and the inhibitory histone mark H3K27me3. Knockdown of OCT4 during differentiation inhibits mesendoderm formation and removal of the H3K27me3 mark from the SOX17 promoter, suggesting that OCT4 acts to induce removal of the PRC2 complex. Furthermore, OCT4 and β-catenin can be co-immunoprecipitated upon differentiation, and Wnt stimulation is required for the enhanced OCT4 occupancy and loss of the PRC2 complex from the SOX17 promoter. In conclusion, our study reveals that OCT4, a master regulator of pluripotency, may also collaborate with Wnt signaling to drive endoderm induction by pre-patterning epigenetic markers on endodermal promoters.
    Stem Cell Reports 09/2015; 5(4). DOI:10.1016/j.stemcr.2015.08.014 · 5.37 Impact Factor
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    • "The architecture of this ''pluripotency network'' is similar in topology to networks in a wide variety of stem cell types (ranging from the MyoD network in myoblasts to the Pu.1 network in monocytes) where a central group of auto-activating transcription factors stabilizes stem cell identity through positive feedback (Fong and Tapscott, 2013; Hnisz et al., 2013; Kueh et al., 2013; Whyte et al., 2013). The pluripotency network is involved in both stabilization of the pluripotent state and lineage selection (Loh and Lim, 2011; Thomson et al., 2011). Lineage selection occurs through a transcription factor competition mechanism (i.e., seesaw model), whereby lineage-specific transcriptional regulators compete for binding with the components of the pluripotency protein "
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    ABSTRACT: Stem cells occupy variable environments where they must distinguish stochastic fluctuations from developmental cues. Here, we use optogenetics to investigate how the pluripotency network in embryonic stem (ES) cells achieves a robust response to differentiation cues but not to gene expression fluctuations. We engineered ES cells in which we could quantitatively ontrol the endogenous mechanism of neural differentiation through a light-inducible Brn2 transgene and monitor differentiation status through a genome-integrated Nanog-GFP reporter. By exposing cells to pulses of Brn2, we find that the pluripotency network rejects Brn2 inputs that are below specific magnitude or duration thresholds, but allows rapid differentiation when both thresholds are satisfied. The filtering properties of the network arise through its positive feedback architecture and the intrinsic half-life of Nanog, which determines the duration threshold in the network. Together our results suggest that the dynamic properties of positive-feedback networks might determine how inputs are classified as signal or noise by stem cells.
    08/2015; 1(2):117-129. DOI:10.1016/j.cels.2015.08.001
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    • "This simple and elegant model, however, does not adequately explain the mechanisms describing the exit from pluripotency, and moreover, a number of recent studies challenge this classical view. First, several studies show that pluripotency factors may have a direct role in promoting differentiation to different cell lineages [2] [3] [4]. These studies raise the possibility that the so-called " pluripotency factors " have a role not only in maintaining self-renewal, but also in driving lineage specification to exit the pluripotent state. "
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    ABSTRACT: Cellular heterogeneity is now considered an inherent property of most stem cell types, including pluripotent stem cells, somatic stem cells, and cancer stem cells, and this heterogeneity can exist at the epigenetic, transcriptional, and posttranscriptional levels. Several studies have indicated that the stochastic activation of signaling networks may promote heterogeneity and further that this heterogeneity may be reduced by their inhibition. But why different cells in the same culture respond in a nonuniform manner to the identical exogenous signals has remained unclear. Recent studies now demonstrate that the cell cycle position directly influences lineage specification and specifically that pluripotent stem cells initiate their differentiation from the G1 phase. These studies suggest that cells in G1 are uniquely “poised” to undergo cell specification. G1 cells are therefore more prone to respond to differentiation cues, which may explain the heterogeneity of developmental factors, such as Gata6, and pluripotency factors, such as Nanog, in stem cell cultures. Overall, this raises the possibility that G1 serves as a “Differentiation Induction Point.” In this review, we will reexamine the literature describing heterogeneity of pluripotent stem cells, while highlighting the role of the cell cycle as a major determinant.
    Stem cell International 05/2015; 2015:1-9. DOI:10.1155/2015/219514 · 2.81 Impact Factor
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