Dataset Information

Topological constraints strongly affect chromatin reconstitution in silico.

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.

SUBMITTER: Brackley CA

PROVIDER: S-EPMC4288149 | biostudies-literature | 2015 Jan

REPOSITORIES: biostudies-literature

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Topological constraints strongly affect chromatin reconstitution in silico.

Brackley C A CA Allan J J Keszenman-Pereyra D D Marenduzzo D D

Nucleic acids research 20141128 1

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 ...[more]

PMID: 25432958

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Project description:BACKGROUND:Current Hi-C technologies for chromosome conformation capture allow to understand a broad spectrum of functional interactions between genome elements. Although significant progress has been made into analysis of Hi-C data to identify biologically significant features, many questions still remain open, in particular regarding potential biological significance of various topological features that are characteristic for chromatin interaction networks. RESULTS:It has been previously observed that promoter capture Hi-C (PCHi-C) interaction networks tend to separate easily into well-defined connected components that can be related to certain biological functionality, however, such evidence was based on manual analysis and was limited. Here we present a novel method for analysis of chromatin interaction networks aimed towards identifying characteristic topological features of interaction graphs and confirming their potential significance in chromatin architecture. Our method automatically identifies all connected components with an assigned significance score above a given threshold. These components can be subjected afterwards to different assessment methods for their biological role and/or significance. The method was applied to the largest PCHi-C data set available to date that contains interactions for 17 haematopoietic cell types. The results demonstrate strong evidence of well-pronounced component structure of chromatin interaction networks and provide some characterisation of this component structure. We also performed an indicative assessment of potential biological significance of identified network components with the results confirming that the network components can be related to specific biological functionality. CONCLUSIONS:The obtained results show that the topological structure of chromatin interaction networks can be well described in terms of isolated connected components of the network and that formation of these components can be often explained by biological features of functionally related gene modules. The presented method allows automatic identification of all such components and evaluation of their significance in PCHi-C dataset for 17 haematopoietic cell types. The method can be adapted for exploration of other chromatin interaction data sets that include information about sufficiently large number of different cell types, and, in principle, also for analysis of other kinds of cell type-specific networks.

Dataset Information

Topological constraints strongly affect chromatin reconstitution in silico.

Publications

Topological constraints strongly affect chromatin reconstitution in silico.

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