4D nucleome equation predicts gene expression controlled by long-range enhancer-promoter interaction

Recent experimental evidence strongly supports that three-dimensional (3D) long-range enhancer-promoter (E-P) interactions have important influences on gene-expression dynamics, but it is unclear how the interaction information is translated into gene expression over time (4D). To address this question, we developed a general theoretical framework (named as a 4D nucleome equation), which integrates E-P interactions on chromatin and biochemical reactions of gene transcription. With this equation, we first present the distribution of mRNA counts as a function of the E-P genomic distance and then reveal a power-law scaling of the expression level in this distance. Interestingly, we find that long-range E-P interactions can induce bimodal and trimodal mRNA distributions. The 4D nucleome equation also allows for model selection and parameter inference. When this equation is applied to the mouse embryonic stem cell smRNA-FISH data and the E-P genomic-distance data, the predicted E-P contact probability and mRNA distribution are in good agreement with experimental results. Further statistical inference indicates that the E-P interactions prefer to modulate the mRNA level by controlling promoter activation and transcription initiation rates. Our model and results provide quantitative insights into both spatiotemporal gene-expression determinants (i.e., long-range E-P interactions) and cellular fates during development.Author summary: Gene expression is an essential biological process in all organisms. Numerous experimental studies have reported that the long-range enhancer-promoter (E-P) interaction on three-dimensional (3D) chromatin architecture plays important roles in regulating gene expression and cell functions, but the quantitative and qualitative impact of E-P interaction on gene expression over time is unclear. We develop a theoretically and numerically efficient model (called the 4D nucleome equation) to couple E-P interaction with gene expression and use this equation to characterize dynamic behavior. Then, we obtain the theoretical distribution of mRNAs and predict the gene expression profiles under E-P regulations. Interestingly, we find that E-P interactions can induce bimodal and trimodal shapes of mRNA distribution. When applying this framework to mouse embryonic stem cell data to investigate the dynamical behaviors of E-P interaction and gene expression, we reproduce the experimentally measured E-P contact frequencies and mRNA distributions under different E-P interactions. Our results support the picture of an essential mechanism for explaining phenotypic diversity and cellular decision-making.