Autocrine FGF feedback can establish distinct states of Nanog expression in pluripotent stem cells: a computational analysis

BMC Systems Biology

Andras Czirok¹  Jay L Vivian³  Kelsey E Pierson³  Emily D Travis³  Dora Lakatos² 

[1] Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, KS, USA;Department of Biological Physics, Eotvos Lorand University, Budapest, Hungary;Division of Cancer and Developmental Biology, Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS, USA

关键词: Regulatory network;    Mitogen-activated protein kinase;    Fibroblast growth factors;    Gene expression heterogeneity;    Transcription factors;    Autocrine signaling;    Computational model;    Stem cell pluripotency;   

Others  :  1092017
DOI  :  10.1186/s12918-014-0112-4

 received in 2014-03-12, accepted in 2014-08-08,  发布年份 2014

【 摘 要 】

Background

The maintenance of stem cell pluripotency is controlled by a core cluster of transcription factors, NANOG, OCT4 and SOX2 – genes that jointly regulate each other’s expression. The expression of some of these genes, especially of Nanog, is heterogeneous in a population of undifferentiated stem cells in culture. Transient changes in expression levels, as well as heterogeneity of the population is not restricted to this core regulator, but involve a large number of other genes that include growth factors, transcription factors or signal transduction proteins.

Results

As the molecular mechanisms behind NANOG expression heterogeneity is not yet understood, we explore by computational modeling the core transcriptional regulatory circuit and its input from autocrine FGF signals that act through the MAP kinase cascade. We argue that instead of negative feedbacks within the core NANOG-OCT4-SOX2 transcriptional regulatory circuit, autocrine signaling loops such as the Esrrb - FGF - ERK feedback considered here are likely to generate distinct sub-states within the “ON” state of the core Nanog switch. Thus, the experimentally observed fluctuations in Nanog transcription levels are best explained as noise-induced transitions between negative feedback-generated sub-states. We also demonstrate that ERK phosphorilation is altered and being anti-correlated with fluctuating Nanog expression – in accord with model simulations. Our modeling approach assigns an empirically testable function to the transcriptional regulators Klf4 and Esrrb, and predict differential regulation of FGF family members.

Conclusions

We argue that slow fluctuations in Nanog expression likely reflect individual cell-specific changes in parameters of an autocrine feedback loop, such as changes in ligand capture efficiency, receptor numbers or the presence of crosstalks within the MAPK signal transduction pathway. We proposed a model that operates with binding affinities of multiple transcriptional regulators of pluripotency, and the activity of an autocrine signaling pathway. The resulting model produces varied expression levels of several components of pluripotency regulation, largely consistent with empirical observations reported previously and in this present work.

【 授权许可】

   
2014 Lakatos et al.; licensee BioMed Central Ltd.

【 图 表 】

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