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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    • "Herein, subsets of pluripotencymaintaining factors have been shown to adopt new roles during lineage specification and have been grouped into neuroectodermal and mesendodermal sets of embryonic stem cell genes [5]. Accordingly, for example, Nanog, Tbx3, Klf5, and Oct3/4 regulate the exit towards mesendoderm while Sox2 regulates differentiation towards a neuroectodermal fate [5]. However, detailed underlying mechanisms of how these TFs orchestrate cell fate decisions remain largely elusive. "
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    ABSTRACT: Pluripotent stem cells are characterised by continuous self-renewal while maintaining the potential to differentiate into cells of all three germ layers. Regulatory networks of maintaining pluripotency have been described in great detail and, similarly, there is great knowledge on key players that regulate their differentiation. Interestingly, pluripotency has various shades with distinct developmental potential, an observation that coined the term of a ground state of pluripotency. A precise interplay of signalling axes regulates ground state conditions and acts in concert with a combination of key transcription factors. The balance between these transcription factors greatly influences the integrity of the pluripotency network and latest research suggests that minute changes in their expression can strengthen but also collapse the network. Moreover, recent studies reveal different facets of these core factors in balancing a controlled and directed exit from pluripotency. Thereby, subsets of pluripotency-maintaining factors have been shown to adopt new roles during lineage specification and have been globally defined towards neuroectodermal and mesendodermal sets of embryonic stem cell genes. However, detailed underlying insights into how these transcription factors orchestrate cell fate decisions remain largely elusive. Our group and others unravelled complex interactions in the regulation of this controlled exit. Herein, we summarise recent findings and discuss the potential mechanisms involved.
    Full-text · Article · Jan 2016 · Stem cell International
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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.
    Full-text · Article · Sep 2015 · Stem Cell Reports
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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.
    Preview · Article · Aug 2015
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