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

Area of Science:

• Genomics
• Systems Biology
• Biophysics

Background:

• Three-dimensional (3D) enhancer-promoter (E-P) interactions are known to influence gene expression dynamics.
• The temporal (4D) translation of these 3D interactions into gene expression remains poorly understood.

Purpose of the Study:

• To develop a theoretical framework that integrates E-P interactions and gene transcription biochemical reactions.
• To quantitatively analyze the spatiotemporal determinants of gene expression.

Main Methods:

• Development of a general theoretical framework, the 4D nucleome equation.
• Integration of enhancer-promoter interactions on chromatin with gene transcription processes.
• Application of the model to mouse embryonic stem cell data (smRNA-FISH and E-P genomic distance).

Main Results:

• The 4D nucleome equation predicts a power-law scaling of mRNA expression with E-P genomic distance.
• Long-range E-P interactions can lead to bimodal and trimodal mRNA distributions.
• Model predictions show good agreement with experimental data for E-P contact probability and mRNA distribution.

Conclusions:

• The 4D nucleome equation provides quantitative insights into how E-P interactions affect gene expression over time.
• E-P interactions primarily modulate mRNA levels by controlling promoter activation and transcription initiation rates.
• The findings offer a deeper understanding of spatiotemporal gene regulation and its role in cellular fate determination.