Theoretical Principles of Enhancer-Promoter Communication in Transcriptional Bursting

Transcriptional regulation occurs through genomic contacts between enhancers and their cognate promoters, and most genes are transcribed in a bursty fashion. To understand the relationship between these two phenomena, we develop a general modeling framework in terms of the information transmission from upstream genomic organization to downstream transcriptional bursting. Importantly, we uncover fundamental theoretical principles of enhancer-promoter (E-P) spatial communication in the modulation of transcriptional burst size (BS) and burst frequency (BF). First, BS and BF obey their respective power-law dependences on the E-P communication strength and distinct scaling exponents. Second, the E-P spatial distance follows a Maxwell-Boltzmann distribution rather than the previously assumed Gauss distribution. Third, the E-P genomic distance affects transcriptional outcomes biphasically (i.e., in an exponential decay for small E-P genomic distances but insensitively to large E-P genomic distances). Fourth, the E-P communication mainly modulates BF rather than BS. Finally, the mutual information between BS (or BF) and E-P spatial distance further reveals essential characteristics of the information transfer from the upstream to the downstream. Our predictions are experimentally verifiable, e.g., confirmed by experimental data on Drosophila. The overall analysis provides insights into the role of the E-P communication in the control of transcriptional bursting. SignificanceMeasurement technologies of chromatin conformations and genome-wide occupancy data of architectural proteins have revealed that genome topology is tightly intertwined with gene transcription. However, a long-standing question in transcriptional regulation is how the enhancer-promoter (E-P) spatial communication impacts transcriptional bursting kinetics. To address this issue, we develop a multiscale model that couples upstream chromatin dynamics to downstream transcriptional bursting. This model not only reveals fundamental principles of E-P communication in transcriptional bursting kinetics (e.g., burst size and frequency follow their own power-law behaviors) but also provides a general modeling framework toward the 4D nucleome project.