Physical mechanisms underlying spatial targeting of chromatin-associated biomolecular condensates

Biomolecular condensates must form in specific small regions in a cell at specific times in order to participate in many biological functions such as DNA transcription. However, the biophysical mechanisms underlying spatio-temporal targeting remain poorly understood. To address this question, we present a coarse-grained model of chromatin-associated transcriptional condensates composed of BRD4 proteins. This model reproduces key experimental observations, including phase diagrams with and without chromatin. We then use equilibrium and nonequilibrium molecular dynamics to understand the physical determinants of the microscopic structure and assembly mechanisms of these condensates. We show how the acetylation of histone tails governs the propensity for spatially targeted condensation, and we identify specific features of wild-type BRD4 that are essential for this behavior. Our model provides molecular-level insights into the assembly of BRD4 transcriptional condensates and suggests general physical requirements for achieving precise spatial targeting of chromatin-associated transcriptional condensates in living cells.