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.