Persistence of Long-Range Contacts at Insulators: Turnover Dynamics or Engaged Cohesin?

Abstract Long-range contacts between distant loci are more frequent for sites colocalizing within the same topological-associating domain (TAD). By contrast, long-range contacts are not favored for sites separated by TAD borders that may define “physical” insulators. Borders are bound by insulator-binding proteins (IBPs). IBPs recruit cofactors like cohesin that can embrace the two distant DNA sites for possible stabilization of the DNA loop, as shown by combining chromosome conformation capture and derivative technologies using deep sequencing (3C/4C/Hi-C). The stability of long-range contacts at insulators may depend on DNA–protein (e.g., insulator-IBP) and protein–protein (e.g., IBP-cofactor) association/dissociation rates (kon–koff) within (insulator 1-IBP1-cofactor-IBP2-insulator 2) complexes that localize at specific nuclear sites called insulator bodies or related, transcription/replication factories. Persistence of long-range contacts at such sites may depend on either (1) at equilibrium dynamics resulting in loops (dis-)assembly depending on binding/dissociation constants or (2) out-of-equilibrium, “committed” DNA–protein interactions as illustrated by the “engaged” cohesin ring when it embraces two sister-chromatids or by the RNA polymerase II when it is paused shortly after initiating transcription, i.e., complexes that might define irreversible reactions. Turnover dynamic studies are thus required to unravel the dynamics of long-range contacts.