The emergence of the two cell fates and their associated switching for a negative auto-regulating gene

Abstract

Background: Decisions in the cell that lead to its ultimate fate are important for fundamental cellular functions such as proliferation, growth, differentiation, development, and death. These cell fate decisions can be influenced by both the gene regulatory network and also environmental factors and can be modeled using simple gene feedback circuits. Negative auto-regulation is a common feedback motif in the gene circuits. It can act to reduce gene expression noise or induce oscillatory expression and is thought to lead to only one cell fate. Here, we present experimental and modeling data to suggest that a self-repressor circuit can lead to two cell fates under specific conditions. Results: We show that the introduction of inducers capable of binding and unbinding to a self-repressing gene product (protein), thus regulating the associated gene, can lead to the emergence of two cell states. We suggest that the inducers can alter the effective regulatory binding and unbinding speed of the self-repressor regulatory protein to its destination DNA without changing the gene itself. The corresponding simulation results are consistent with the experimental findings. We propose physical and quantitative explanations for the origin of the two phenotypic cell fates. Conclusions: Our results suggest a mechanism for the emergence of multiple cell fates. This may explain the heterogeneity often observed among cell states, while illustrating that altering gene regulation strength can influence cell fates and their decision-making processes without genetic changes.