Dissecting mechanisms of mouse embryonic stem cells heterogeneity through a model-based analysis of transcription factor dynamics.
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.
Institute for Medical Informatics and Biometry, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany Interdisciplinary Center for Bioinformatics, Faculty of Medicine, Universität Leipzig, Leipzig, Germany maria.herberg@uni-leipzig.de.
Maria
M
Herberg
Institute for Medical Informatics and Biometry, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
Ingmar
I
Glauche
Institute for Medical Informatics and Biometry, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
Thomas
T
Zerjatke
University Cancer Center, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
Maria
M
Winzi
University Cancer Center, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
Frank
F
Buchholz
Institute for Medical Informatics and Biometry, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
Ingo
I
Roeder
D000818:Animals; D002460:Cell Line; D005786:Gene Expression Regulation / Q000502:physiology*; D051379:Mice; D008954:Models, Biological; D000066450:Mouse Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism; D000071317:Nanog Homeobox Protein / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic / Q000502:physiology*
D000071317:Nanog Homeobox Protein; C475540:Nanog protein, mouse; C513672:Zfp42 protein, mouse; D014157:Transcription Factors
Nanog heterogeneity; agent-based modelling; cellular genealogies; flow cytometry; oscillations