A conserved thermodynamic signature links transcriptome organization to growth state

Abstract

Living systems operate far from thermodynamic equilibrium, sustaining complexity through continuous free-energy influx and heat dissipation. Yet the higher-order functional constraints imposed by non-equilibrium dynamics remain largely unexplored. To formalize how changes in cellular entropy production constrain intracellular organization across proliferative state transitions, we developed a stochastic-thermodynamic model linking reduced dissipative drive to transient increases in intracellular configurational entropy. Within this framework, we examined abundance-weighted predicted RNA folding stability as a transcriptome-level projection of the intracellular configurational remodelling. Consistent with the model, transcriptome reorganization across the cell cycle produces coordinated, phase-dependent changes in the distribution of transcript-level RNA folding free energies. Extending this analysis to stress adaptation, we find that human cancer cells exposed to molecularly targeted agents and nutrient-limited Escherichia coli converge on expressed RNA pools enriched for transcripts with less negative RNA folding free energies, despite marked heterogeneity in the transcriptional responses within each system. Opposing shifts during acquired resistance under continued drug exposure and bacterial recovery from starvation further support an association with growth state. Together, these findings suggest that transcriptome organization extends beyond gene-regulatory programs to collective biophysical properties that may reflect non-equilibrium constraints shaping cellular-state transitions.