Abstract
A remarkable feature of the self-renewing population of embryonic stem cells (ESCs) is their phenotypic heterogeneity: Nanog and other marker proteins of ESCs show large cell-to-cell variation in their expression level, which should significantly influence the differentiation process of individual cells. The molecular mechanism and biological implication of this heterogeneity, however, still remain elusive. We address this problem by constructing a model of the core gene-network of mouse ESCs. The model takes account of processes of binding/unbinding of transcription factors, formation/dissolution of transcription apparatus, and modification of histone code at each locus of genes in the network. These processes are hierarchically interrelated to each other forming the dynamical feedback loops. By simulating stochastic dynamics of this model, we show that the phenotypic heterogeneity of ESCs can be explained when the chromatin at the Nanog locus undergoes the large scale reorganization in formation/dissolution of transcription apparatus, which should have the timescale similar to the cell cycle period. With this slow transcriptional switching of Nanog, the simulated ESCs fluctuate among multiple transient states, which can trigger the differentiation into the lineage-specific cell states. From the simulated transitions among cell states, the epigenetic landscape underlying transitions is calculated. The slow Nanog switching gives rise to the wide basin of ESC states in the landscape. The bimodal Nanog distribution arising from the kinetic flow running through this ESC basin prevents transdifferentiation and promotes the definite decision of the cell fate. These results show that the distribution of timescales of the regulatory processes is decisively important to characterize the fluctuation of cells and their differentiation process. The analyses through the epigenetic landscape and the kinetic flow on the landscape should provide a guideline to engineer cell differentiation.
Highlights
Embryonic stem cells (ESCs) are pluripotent having the ability to differentiate into a variety of lineages, while in suitable culture conditions they proliferate indefinitely by maintaining pluripotency
Before starting the explanation of the simulated results, we briefly explain the interaction network among genes considered in the present model and discuss the dynamics of each gene in the network in subsection Gene network and epigenetic dynamics
To identify each elementary interaction embedded in the complex web of regulation
Summary
Embryonic stem cells (ESCs) are pluripotent having the ability to differentiate into a variety of lineages, while in suitable culture conditions they proliferate indefinitely by maintaining pluripotency. These self-renewing ESCs are distinguished by the marker proteins including Sox, Oct and Nanog (SON) [1,2,3,4]. Since a distinct downregulation of Nanog is associated with the differentiation of ESCs into mesendoderm or neural ectoderm lineages [16], the heterogeneous Nanog expression can be intimately related to the process of fate decision of individual cells [14,17].
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