Chromatin-loop extrusion and chromatin unknotting

Abstract

It has been a puzzle how decondensed interphase chromosomes remain essentially unknotted. The natural expectation is that in the presence of type II DNA topoisomerases that permit passages of double-stranded DNA regions through each other, all chromosomes should reach the state of topological equilibrium. The topological equilibrium in highly crowded interphase chromosomes forming chromosome territories would result in formation of highly knotted chromatin fibres. However, Chromosome Conformation Capture (3C) methods revealed that the decay of contacts with the genomic distance in interphase chromosomes is practically the same as in the crumpled globule state that is formed when long polymers condense without formation of any knots. To remove knots from highly crowded chromatin, one would need an active process that should not only provide the energy to move the system from the state of topological equilibrium but also guide topoisomerase-mediated passages in such a way that knots would be efficiently unknotted instead of making the knots even more complex. We show here that the process of chromatin-loop extrusion is ideally suited to actively unknot chromatin fibres in interphase chromosomes.\n\nSIGNIFICANCE STATEMENTSimilar to earphone cables crammed into a pocket, long and crowded chromatin fibres that form chromosomes in living cells have the natural tendency to get knotted. This is exacerbated by the action of DNA topoisomerases that transiently cut some chromatin fibres and let other to pass through. Yet, the knotting frequency of chromatin fibres is very low and it has been a puzzle how this is achieved. Recently a novel active mechanism known as chromatin loop extrusion has been proposed to be involved in shaping chromosomes by forming sequential arrays of ca 1 Mb large chromatin loops. Using numerical simulations, we show here that chromatin loop extrusion is ideally suited to remove knots from chromatin fibres.