Dissecting mechanisms of mouse embryonic stem cells heterogeneity through a model-based analysis of transcription factor dynamics

Authored by Ingo Roeder, Maria Herberg, Ingmar Glauche, Thomas Zerjatke, Maria Winzi, Frank Buchholz

Date Published: 2016

DOI: 10.1098/rsif.2016.0167

Sponsors: European Union German Research Foundation (Deutsche Forschungsgemeinschaft, DFG)

Platforms: No platforms listed

Model Documentation: Other Narrative

Model Code URLs: Model code not found

Abstract

Pluripotent mouse embryonic stem cells (mESCs) show heterogeneous expression levels of transcription factors (TFs) involved in pluripotency regulation, among them Nanog and Rex1. The expression of both TFs can change dynamically between states of high and low activity, correlating with the cells' capacity for self-renewal. Stochastic fluctuations as well as sustained oscillations in gene expression are possible mechanisms to explain this behaviour, but the lack of suitable data hampered their clear distinction. Here, we present a systems biology approach in which novel experimental data on TF heterogeneity is complemented by an agent-based model of mESC self-renewal. Because the model accounts for intracellular interactions, cell divisions and heredity structures, it allows for evaluating the consistency of the proposed mechanisms with data on population growth and on TF dynamics after cell sorting. Our model-based analysis revealed that a bistable, noise-driven network model fulfils the minimal requirements to consistently explain Nanog and Rex1 expression dynamics in heterogeneous and sorted mESC populations. Moreover, we studied the impact of TF-related proliferation capacities on the frequency of state transitions and demonstrate that cellular genealogies can provide insights into the heredity structures of mESCs.

Tags

differentiation Culture Network Self-renewal Ground-state Nanog Pluripotency Sox2 Depends Oct4