Theoretical Principles of Enhancer-Promoter Communication in Transcriptional Bursting

Abstract 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. Significance Measurement 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.