Quantitative dissection of transcription in development yields evidence for transcription-factor-driven chromatin accessibility.

Abstract

Thermodynamic models of gene regulation can predict transcriptional regulation in bacteria, but in eukaryotes, chromatin accessibility and energy expenditure may call for a different framework. Here, we systematically tested the predictive power of models of DNA accessibility based on the Monod-Wyman-Changeux (MWC) model of allostery, which posits that chromatin fluctuates between accessible and inaccessible states. We dissected the regulatory dynamics of <i>hunchback</i> by the activator Bicoid and the pioneer-like transcription factor Zelda in living <i>Drosophila</i> embryos and showed that no thermodynamic or non-equilibrium MWC model can recapitulate <i>hunchback</i> transcription. Therefore, we explored a model where DNA accessibility is not the result of thermal fluctuations but is catalyzed by Bicoid and Zelda, possibly through histone acetylation, and found that this model can predict <i>hunchback</i> dynamics. Thus, our theory-experiment dialogue uncovered potential molecular mechanisms of transcriptional regulatory dynamics, a key step toward reaching a predictive understanding of developmental decision-making.