Cell fate potentials and switching kinetics uncovered in a classic bistable genetic switch

Xiaona Fang,Zach Hensel,Jie Xiao,Christopher Bohrer,Wei Han,Qiong Liu,Jin Wang

doi:10.1038/s41467-018-05071-1

Abstract

Bistable switches are common gene regulatory motifs directing two mutually exclusive cell fates. Theoretical studies suggest that bistable switches are sufficient to encode more than two cell fates without rewiring the circuitry due to the non-equilibrium, heterogeneous cellular environment. However, such a scenario has not been experimentally observed. Here by developing a new, dual single-molecule gene-expression reporting system, we find that for the two mutually repressing transcription factors CI and Cro in the classic bistable bacteriophage λ switch, there exist two new production states, in which neither CI nor Cro is produced, or both CI and Cro are produced. We construct the corresponding potential landscape and map the transition kinetics among the four production states. These findings uncover cell fate potentials beyond the classical picture of bistable switches, and open a new window to explore the genetic and environmental origins of the cell fate decision-making process in gene regulatory networks.

Highlights

Bistable switches are common gene regulatory motifs directing two mutually exclusive cell fates
Theoretical studies suggest that the simple circuitry of bistable switches is sufficient to encode more than two cell fates due to the non-equilibrium, heterogeneous cellular environment, allowing a high degree of adaptation and differentiation[13,14,15,16]
New cell fates arising from a classic bistable switch without rewiring the circuitry have not been experimentally observed[17,18,19]

Summary

Introduction

Bistable switches are common gene regulatory motifs directing two mutually exclusive cell fates. In the dual gene-expression reporting system, we fused a fastmaturing yellow fluorescent protein variant, Venus[22], to one of two cellular localization tags, Tsr or LacI, to distinguish the production of CI and Cro in the same cell.

Results

Conclusion