Elastic enhancer network tunes equilibrium thermodynamics of liquid liquid phase separation in super enhancers

Super-enhancers (SEs) are clusters of enhancers that drive higher transcriptional output than typical enhancers (TEs) and regulate key genes central to cell type-specific gene expression programs. Liquid-liquid phase separation (LLPS) mediates the formation of SE-associated droplets with distinct functional properties. Here, we develop a theoretical framework in which chromatin architecture mechanically constrains LLPS droplet growth. Quantitative modeling within a binary phase separation system shows that the growth increment scales as Δ R ∝ k − 1 / 2 , where k denotes the interaction strength between enhancer elements, thereby limiting droplet growth and supporting SE size homeostasis in the nucleus. Model predictions agree quantitatively with experiments and indicate that mechanical constraints regulate the critical concentration and miscibility of SE-associated droplets. Mechanical constraints may potentially regulate local concentration by altering the osmotic pressure difference across the droplet interface, which may in turn modulate transcriptional activity.