Decoding the role of DNA sequence on protein-DNA co-condensation

The eukaryotic genome is organized within the cell nucleus through three-dimensional compaction. The physical principles that govern genome organization in vivo remain less understood. Phase separation of protein and DNA has emerged as an attractive mechanism for reshaping chromatin and compacting the genome. In vitro studies have shed light on the biophysical principles of protein-DNA condensates driven by protein-protein and protein-DNA interactions. However, the role of DNA sequence and its impact on protein-DNA condensation remains elusive. Guided by experiments, this paper presents a simple polymer-based model of protein-mediated DNA condensation that explicitly incorporates the influence of DNA sequence on protein binding. Using coarse-grained Brownian dynamics simulations, we demonstrate that, in the case of a homogeneous DNA, only one condensate forms in equilibrium. In sharp contrast, DNA sequence heterogeneity can result in the coexistence of multiple condensates, giving rise to the formation of structures resembling pearl-necklaces. Interestingly, we observe that protein binding affinity of interfacial DNA governs the capillary forces arising from the protein-DNA condensates. To demonstrate the usefulness of our modeling framework, we compare the simulation results against published data for co-condensation of Dps, Sox2, and HP1. We find that while Dps exhibits sequence-independent binding, DNA sequence heterogeneity dictates the co-condensation of Sox2 and HP1 with DNA. Overall, the framework developed here can be harnessed to gain mechanistic insights into the role of DNA sequence on protein-DNA co-condensation and pave the way for developing a deeper understanding of genome organisation.