title: Ephemeral Protein Binding to DNA Shapes Stable Nuclear Bodies and Chromatin Domains.
abstract: Fluorescence microscopy reveals that the contents of many (membrane-free) nuclear bodies exchange rapidly with the soluble pool while the underlying structure persists; such observations await a satisfactory biophysical explanation. To shed light on this, we perform large-scale Brownian dynamics simulations of a chromatin fiber interacting with an ensemble of (multivalent) DNA-binding proteins able to switch between an "on" (binding) and an "off" (nonbinding) state. This system provides a model for any DNA-binding protein that can be posttranslationally modified to change its affinity for DNA (e.g., through phosphorylation). Protein switching is a nonequilibrium process, and it leads to the formation of clusters of self-limiting size, where individual proteins in a cluster exchange with the soluble pool with kinetics similar to those seen in photobleaching experiments. This behavior contrasts sharply with that exhibited by nonswitching proteins, which are permanently in the on-state; when these bind to DNA nonspecifically, they form clusters that grow indefinitely in size. To explain these findings, we propose a mean-field theory from which we obtain a scaling relation between the typical cluster size and the protein switching rate. Protein switching also reshapes intrachromatin contacts to give networks resembling those seen in topologically associating domains, as switching markedly favors local (short-range) contacts over distant ones. Our results point to posttranslational modification of chromatin-bridging proteins as a generic mechanism driving the self-assembly of highly dynamic, nonequilibrium, protein clusters with the properties of nuclear bodies.
authors.affiliation: SUPA, School of Physics and Astronomy, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Chris A
authors.initials: CA
authors.lastname: Brackley
authors.affiliation: SUPA, School of Physics and Astronomy, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Benno
authors.initials: B
authors.lastname: Liebchen
authors.affiliation: SUPA, School of Physics and Astronomy, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Davide
authors.initials: D
authors.lastname: Michieletto
authors.affiliation: SUPA, School of Physics and Astronomy, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Francois
authors.initials: F
authors.lastname: Mouvet
authors.affiliation: Sir William Dunn School of Pathology, University of Oxford, Oxford, United Kingdom.
authors.forename: Peter R
authors.initials: PR
authors.lastname: Cook
authors.affiliation: SUPA, School of Physics and Astronomy, University of Edinburgh, Edinburgh, United Kingdom. Electronic address: dmarendu@ph.ed.ac.uk.
authors.forename: Davide
authors.initials: D
authors.lastname: Marenduzzo
mesh_terms: D002467:Cell Nucleus / Q000378:metabolism*; D002843:Chromatin / Q000378:metabolism*; D004247:DNA / Q000737:chemistry / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000378:metabolism*; D008856:Microscopy, Fluorescence; D008958:Models, Molecular; D009690:Nucleic Acid Conformation; D011485:Protein Binding; D011487:Protein Conformation
chemical_list: D002843:Chromatin; D004268:DNA-Binding Proteins; D004247:DNA