Protein search processes mediated by chromatin topology

Abstract

AbstractWe investigate the role of compaction of chromatin domains in modulating search kinetics of proteins. Collapsed conformations of chromatin, characterised by long loops which bring distant regions of the genome into contact, and manifested structurally as Topologically Associated Domains (TADs) affect search kinetics of DNA associated transcription factors and other proteins. In this study, we investigate the role of the compactness of chromatin on the dynamics of proteins using a minimal model. Using theory and simulations, we show that an optimal compaction exists for which the residence time of proteins on a chromatin-like polymer backbone is minimum. We then show that the fraction of unique sites visited also shows a similar non-monotonic behavior as a function of the polymer compaction. We extend these results to more detailed polymer models - using the Freely Rotating Chain model, a Lennard-Jones bead-spring polymer, and a soft polymer chain model, which approximates chromatin behavior. We show that our results continue to hold for these polymer models, with a minimum residence time at an optimum polymer compaction. Finally, we also analyse the dynamics of proteins on networks generated using experimental chromatin conformation data for several TADs extracted from human chromosomes. Our analysis suggests that TADs exist near this zone of optimality, indicating that chromatin conformations can play a crucial role in modulating protein search strategies.