A stochastic and dynamical view of pluripotency in mouse embryonic stem cells

TL;DR

This paper presents a new framework for modeling pluripotency in mouse embryonic stem cells, incorporating gene network dynamics and molecular noise to better understand cell state stability and transition mechanisms.

Contribution

It introduces a mechanistic modeling approach that extends boolean gene networks to include stochastic gene switching and promoter architecture, revealing insights into pluripotency stability and differentiation.

Findings

Pluripotent state acts as a broad, robust attractor.

Molecular noise influences exit dynamics and cell responsiveness.

Global gene switching rates can remodel the stability landscape.

Abstract

Pluripotent embryonic stem cells are of paramount importance for biomedical research thanks to their innate ability for self-renewal and differentiation into all major cell lines. The fateful decision to exit or remain in the pluripotent state is regulated by complex genetic regulatory network. Latest advances in transcriptomics have made it possible to infer basic topologies of pluripotency governing networks. The inferred network topologies, however, only encode boolean information while remaining silent about the roles of dynamics and molecular noise in gene expression. These features are widely considered essential for functional decision making. Herein we developed a framework for extending the boolean level networks into models accounting for individual genetic switches and promoter architecture which allows mechanistic interrogation of the roles of molecular noise, external signaling, and network topology. We demonstrate the pluripotent state of the network to be a broad attractor which is robust to variations of gene expression. Dynamics of exiting the pluripotent state, on the other hand, is significantly influenced by the molecular noise originating from genetic switching events which makes cells more responsive to extracellular signals. Lastly we show that steady state probability landscape can be significantly remodeled by global gene switching rates alone which can be taken as a proxy for how global epigenetic modifications exert control over stability of pluripotent states.