Pluripotency gene network dynamics: System views from parametric analysis

Abstract

Multiple experimental data demonstrated that the core gene network orchestrating self-renewal and differentiation of mouse embryonic stem cells involves activity of Oct4, Sox2 and Nanog genes by means of a number of positive feedback loops among them. However, recent studies indicated that the architecture of the core gene network should also incorporate negative Nanog autoregulation and might not include positive feedbacks from Nanog to Oct4 and Sox2. Thorough parametric analysis of the mathematical model based on this revisited core regulatory circuit identified that there are substantial changes in model dynamics occurred depending on the strength of Oct4 and Sox2 activation and molecular complexity of Nanog autorepression. The analysis showed the existence of four dynamical domains with different numbers of stable and unstable steady states. We hypothesize that these domains can constitute the checkpoints in a developmental progression from naïve to primed pluripotency and vice versa. During this transition, parametric conditions exist, which generate an oscillatory behavior of the system explaining heterogeneity in expression of pluripotent and differentiation factors in serum ESC cultures. Eventually, simulations showed that addition of positive feedbacks from Nanog to Oct4 and Sox2 leads mainly to increase of the parametric space for the naïve ESC state, in which pluripotency factors are strongly expressed while differentiation ones are repressed.

FGF Signaling Pathway: A Key Regulator of Stem Cell Pluripotency

“…Pluripotency maintenance in ESCs and iPSCs are provided by inhibiting the signaling pathways governing the differentiation potential of the stem cells (Akberdin et al, 2018).…”

OCT4 expression in human embryonic stem cells: spatio-temporal dynamics and fate transitions

“…To visualise the OCT4 values in relation to the previous time frame we use Poincaré plots, but note that other methods are also applicable here, such as diffusion maps [81]. An autocorrelation analysis shows periods of anti-correlation, in keeping with the regulation of pluripotency TFs [2,35,82]. Throughout the colony growth, anti-correlation of at least five hours is seen in 86% of cells (with no significant difference between the cell fates) and on average occurs between 3 and 12 hours into a cell's lifetime.…”

Fine‐tuning Nanog expression heterogeneity in embryonic stem cells by regulating a Nanog transcript‐specific microRNA

“…Over the last few decades, several network models with increasing complexities had been proposed [29][30][31][32] to decipher the underlying network dynamics that control the core transcriptional regulation in ESCs by explaining the state-of-the-art experimental data. Even the heterogeneous Nanog gene expression and reprogramming efficiency had been analyzed with great details by considering the stochastic modeling setup [6].…”

“…The effect of the inhibitors to this transcriptional network is mostly modeled phenomenologically to reproduce the experimentally observed heterogeneity in Nanog transcriptional regulation. However, our previous model of core Nanog transcriptional regulation lacks various important interactions (such as Nanog autorepression [41], the repressive effect of Oct4/Sox2 at high Oct4 concentration [42], and related Nanog and Oct4/Sox2 autoregulation [4,32] that is known experimentally).…”