Abstract
The fundamental building block of chromatin, and of chromosomes, is the nucleosome, a composite material made up from DNA wrapped around a histone octamer. In this study we provide the first computer simulations of chromatin self-assembly, starting from DNA and histone proteins, and use these to understand the constraints which are imposed by the topology of DNA molecules on the creation of a polynucleosome chain. We take inspiration from the in vitro chromatin reconstitution protocols which are used in many experimental studies. Our simulations indicate that during self-assembly, nucleosomes can fall into a number of topological traps (or local folding defects), and this may eventually lead to the formation of disordered structures, characterised by nucleosome clustering. Remarkably though, by introducing the action of topological enzymes such as type I and II topoisomerase, most of these defects can be avoided and the result is an ordered 10-nm chromatin fibre. These findings provide new insight into the biophysics of chromatin formation, both in the context of reconstitution in vitro and in terms of the topological constraints which must be overcome during de novo nucleosome formation in vivo, e.g. following DNA replication or repair.
Highlights
Chromatin is the functional form of DNA within the nuclei of eukaryotic cells, and it is the building block of chromosomes
We suggest that the topological transformations between local twist and writhe in the chromatin fibre, which we can follow clearly by analysing the reconstitution dynamics in silico, are at the basis of the finding that topo-I and topoII can relax positively supercoiled yeast circular minichromosomes [49] (we note that the authors of [49,50] propose a similar explanation for their results)
Our results provide a strong suggestion that topological considerations are key to the biophysics of chromatin assembly on linear, as well as on circular, DNA, at least when the dynamics of local rearrangements and strand collision occur over shorter time scales than those required for the equilibration of the whole chromatin fibre
Summary
Chromatin is the functional form of DNA within the nuclei of eukaryotic cells, and it is the building block of chromosomes It is a composite material made up, in its simplest form, of DNA wrapped around positively charged histone octamers [1]. Additional interactions, mediated by histone H1 and other proteins, lead to further compaction, either into the so-called 30-nm fibre [2], or into more complex and less-ordered structures [4,5] Despite this hierarchical packaging, the DNA must remain accessible since, for example, transcription requires the local displacement of histones from the DNA to allow other proteins, such as polymerases, to bind [6]. During replication nucleosomes must be displaced as the replication fork passes, with new nucleosomes assembled on the newly replicated DNA
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