Mechanisms of sensitive and selective nucleation of chromatin-associated biomolecular condensates

In order to perform useful biological functions, phase-separated biomolecular condensates comprising proteins and RNAs must assemble at specific locations within a living cell. However, the biophysical mechanisms by which such spatial control is achieved remain poorly understood. To address this question, we present an experimentally motivated coarse-grained model of a class of transcriptional condensates that are believed to play a role in initiating DNA transcription. Specifically, we consider transcriptional condensates composed of the bromodomain protein BRD4, which selectively associates with chromatin via specific interactions with acetylated histone tails. Through a combination of equilibrium and nonequilibrium molecular dynamics simulations, we elucidate how BRD4–chromatin interactions tune both the partitioning of chromatin into BRD4 condensates and the nucleation pathway by which BRD4 condensates assemble. We show that both the patterning of histone acetylation marks and the oligomerization state of BRD4 molecules govern the sensitivity and specificity of chromatin-seeded heterogeneous nucleation, whereas disruption of BRD4–chromatin interactions suppresses the chromatin-associated nucleation pathway. Our findings provide a molecularly detailed view of the biophysical mechanisms governing BRD4 condensate formation and suggest potential strategies for regulating transcription via spatiotemporal control of transcriptional condensate nucleation.