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

Area of Science:

• Biophysics
• Genomics
• Computational Biology

Background:

• Protein-DNA co-condensation is crucial for chromatin organization and genome architecture.
• The influence of DNA sequence on protein-DNA condensation remains largely unexplored.
• Existing experimental studies offer limited insight into sequence-dependent binding effects.

Purpose of the Study:

• To develop a polymer-based model for protein-DNA co-condensation that incorporates sequence-dependent protein binding.
• To investigate how DNA sequence heterogeneity influences the formation and number of protein-DNA condensates.
• To explore the role of interfacial DNA binding affinity in regulating chromatin structure.

Main Methods:

• Coarse-grained Brownian dynamics simulations of protein-DNA co-condensation.
• Development of a polymer model explicitly accounting for sequence-dependent protein binding.
• Comparison of simulation results with experimental data for Dps, Sox2, and HP1 proteins.

Main Results:

• Homogeneous DNA forms a single condensate, while sequence heterogeneity leads to multiple coexisting condensates.
• Interfacial DNA binding affinity modulates capillary forces, impacting chromatin structure.
• DNA sequence was found to dictate the condensation of Sox2 and HP1 with DNA.

Conclusions:

• DNA sequence heterogeneity is a key factor in regulating the number of protein-DNA condensates.
• The developed model provides mechanistic insights into sequence-dependent protein-DNA interactions.
• This framework advances the understanding of genome organization and chromatin dynamics.