Nonmodular oscillator and switch based on RNA decay drive regeneration of multimodal gene expression

• Published in: Nucleic acids research Vol. 50; no. 7; pp. 3693 - 3708
• Main Authors: Nordick, Benjamin, Yu, Polly Y, Liao, Guangyuan, Hong, Tian
• Format: Journal Article
• Language: English
• Published: England Oxford University Press 22.04.2022
• Subjects: Animals; Computational Biology; Feedback; Feedback, Physiological; Gene Expression; Gene Regulatory Networks; Humans; Mammals; Models, Biological; RNA Stability
• ISSN: 0305-1048; 1362-4962
• DOI: 10.1093/nar/gkac217

Abstract Periodic gene expression dynamics are key to cell and organism physiology. Studies of oscillatory expression have focused on networks with intuitive regulatory negative feedback loops, leaving unknown whether other common biochemical reactions can produce oscillations. Oscillation and noise have been proposed to support mammalian progenitor cells’ capacity to restore heterogenous, multimodal expression from extreme subpopulations, but underlying networks and specific roles of noise remained elusive. We use mass-action-based models to show that regulated RNA degradation involving as few as two RNA species—applicable to nearly half of human protein-coding genes—can generate sustained oscillations without explicit feedback. Diverging oscillation periods synergize with noise to robustly restore cell populations’ bimodal expression on timescales of days. The global bifurcation organizing this divergence relies on an oscillator and bistable switch which cannot be decomposed into two structural modules. Our work reveals surprisingly rich dynamics of post-transcriptional reactions and a potentially widespread mechanism underlying development, tissue regeneration, and cancer cell heterogeneity. Graphical Abstract Graphical Abstract An RNA-centric reaction network generates oscillation and bistability via sequential binding and cooperative decay without explicit feedback. The oscillation has diverging periods and it can synergize with noise to support robust recovery of multimodal gene expression in a cell population on timescales of days.