Flexibility and sensitivity in gene regulation out of equilibrium

Cells adapt to environments and tune gene expression by controlling the concentrations of proteins and their kinetics in regulatory networks. In both eukaryotes and prokaryotes, experiments and theory increasingly attest that these networks can and do consume bio-chemical energy. How does this dissipation enable cellular behaviors unobtainable in equilibrium? This open question demands quantitative models that transcend thermodynamic equilibrium. Here we study the control of a simple, ubiquitous gene regulatory motif to explore the consequences of departing equilibrium in kinetic cycles. Employing graph theory, we find that dissipation unlocks nonmonotonicity and enhanced sensitivity of gene expression with respect to a transcription factor’s concentration. These features allow a single transcription factor to act as both a repressor and activator at different levels or achieve outputs with multiple concentration regions of locally-enhanced sensitivity. We systematically dissect how energetically-driving individual transitions within regulatory networks, or pairs of transitions, generates more adjustable and sensitive phenotypic responses. Our findings quantify necessary conditions and detectable consequences of energy expenditure. These richer mathematical behaviors—feasibly accessed using biological energy budgets and rates—may empower cells to accomplish sophisticated regulation with simpler architectures than those required at equilibrium. Significance Statement Growing theoretical and experimental evidence demonstrates that cells can (and do) spend biochemical energy while regulating their genes. Here we explore the impact of departing from equilibrium in simple regulatory cycles, and learn that beyond increasing sensitivity, dissipation can unlock more flexible input-output behaviors that are otherwise forbidden without spending energy. These more complex behaviors could enable cells to perform more sophisticated functions using simpler systems than those needed at equilibrium. ### Competing Interest Statement The authors have declared no competing interest.