A BASELINE MODEL OF POLYMER-DRIVEN TRANSCRIPTION FOR ENHANCER-DRIVEN GENE ACTIVATION
Henrik D Pinholt1,2, TimothyFoldes2, LeonidMirny1,2
1Massachusetts Institute of Technology, Department of Physics, Cambridge, MA
2Massachusetts Institute of Technology, Institute for Medical Engineering and Science, Cambridge, MA
Enhancers are key regulators of cellular decisions. They manage to convert transcription factor binding into target promoter activation with high fidelity in both space and time. Despite their prevalence and importance, the mechanism of enhancer-driven gene activation remains elusive. Bulk results demonstrate a decrease in transcription upon enhancer-promoter separation, suggesting a proximity-based activation mechanism. However, direct visualization of enhancer-promoter distance along with transcription does not always confirm this picture. Currently, it is unclear whether these results are compatible and whether they are consistent with a picture where enhancer-proximity drives promoter activation. To address these questions, we developed a simple model of enhancer-driven transcription. The model employs a Rouse model for polymer kinetics and considers a promoter that can activate only when the enhancer and promoter come within a threshold distance. We find that experimental data constrain the model to a regime where promoters display low sensitivity to enhancer contacts, requiring several contacts before successful gene activation. This implies a vanishing relation between enhancer-promoter distance and promoter state, providing a possible explanation for the sometimes-lacking correlation between enhancer-promoter distance and transcription observed in experiments. We then investigated how transcription varies with genomic separation and found average transcription and bursting kinetics to be simple hill functions of the contact probability. Interestingly, this allows for easy exploration of the effects of complex enhancer-promoter landscapes on gene activation. Together, these results provide a baseline model of enhancer-driven transcription that answers the question of what to expect when activation is governed by polymer-contacts alone.