Chalmers Conferences, 9th European Conference on Mathematical and Theoretical Biology

Autocrine FGF feedback can establish distinct states of Nanog expression in pluripotent stem cells
Dora Lakatos

Last modified: 2014-03-31


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. 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.