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.
Highlights
Pluripotency is a temporal state in embryogenesis artificially maintained in embryonic stem cells (ESCs) by specific components in the medium providing ESC self-renewal and inhibition of signaling pathways driving differentiation
Pluripotency gene network dynamics: System views from parametric analysis biased correspondingly to pluripotency and differentiation
Multiple experimental studies demonstrate that Oct4, Sox2 and Nanog (OSN) are the core factors in pluripotency gene network involved in induction, maintenance and loss of pluripotency
Summary
Pluripotency is a temporal state in embryogenesis artificially maintained in embryonic stem cells (ESCs) by specific components in the medium providing ESC self-renewal and inhibition of signaling pathways driving differentiation (reviewed in [1, 2, 3]). In mouse pluripotent cells there are three types of media used for this, 2i/LIF, serum/LIF and FGF2/Activin providing for naïve, formative and primed pluripotent states, respectively. These states differ in the expression of pluripotency and differentiation genes with naïve and primed states. Multiple experimental studies demonstrate that Oct, Sox and Nanog (OSN) are the core factors in pluripotency gene network involved in induction, maintenance and loss of pluripotency (reviewed in [2, 9])
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.