Controlled targeting of chromatin-associated biomolecular condensates via co-condensation and multivalency

Biomolecular condensates must nucleate at specific locations inside a living cell in order to perform their biological functions, such as regulating DNA transcription. However, the molecular mechanisms that enable specific and robust spatial control of condensate nucleation remain poorly understood. To uncover such mechanisms in the context of chromatin-associated condensates, we develop an ultra-coarse-grained molecular-dynamics model of BRD4 proteins and chromatin. Our model predicts that co-condensation of BRD4 and chromatin is key to the formation of chromatin-associated condensates at low BRD4 concentrations. This effect allows for highly specific and rapid nucleation of BRD4 condensates at regions of chromatin with highly acetylated histone tails. Additionally, we find that multivalent binding of wild-type BRD4 to acetylated histone tails further enhances the sensitivity of BRD4 condensate to changes in acetylation levels. Our model provides a microscopic view of the structure and dynamics of BRD4-chromatin condensates and suggests how the interplay between multivalency and co-condensation leads to precise spatiotemporal control over condensate formation.