Hi-C implementation of genome structure for in silico models of radiation-induced DNA damage

Developments in the genome organisation field has resulted in the recent methodology to infer spatial conformations of the genome directly from experimentally measured genome contacts (Hi-C data). This provides a detailed description of both intra- and inter-chromosomal arrangements. Chromosomal int...

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Veröffentlicht in:PLoS computational biology 2020-12, Vol.16 (12), p.e1008476-e1008476
Hauptverfasser: Ingram, Samuel P, Henthorn, Nicholas T, Warmenhoven, John W, Kirkby, Norman F, Mackay, Ranald I, Kirkby, Karen J, Merchant, Michael J
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container_title PLoS computational biology
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creator Ingram, Samuel P
Henthorn, Nicholas T
Warmenhoven, John W
Kirkby, Norman F
Mackay, Ranald I
Kirkby, Karen J
Merchant, Michael J
description Developments in the genome organisation field has resulted in the recent methodology to infer spatial conformations of the genome directly from experimentally measured genome contacts (Hi-C data). This provides a detailed description of both intra- and inter-chromosomal arrangements. Chromosomal intermingling is an important driver for radiation-induced DNA mis-repair. Which is a key biological endpoint of relevance to the fields of cancer therapy (radiotherapy), public health (biodosimetry) and space travel. For the first time, we leverage these methods of inferring genome organisation and couple them to nano-dosimetric radiation track structure modelling to predict quantities and distribution of DNA damage within cell-type specific geometries. These nano-dosimetric simulations are highly dependent on geometry and are benefited from the inclusion of experimentally driven chromosome conformations. We show how the changes in Hi-C contract maps impact the inferred geometries resulting in significant differences in chromosomal intermingling. We demonstrate how these differences propagate through to significant changes in the distribution of DNA damage throughout the cell nucleus, suggesting implications for DNA repair fidelity and subsequent cell fate. We suggest that differences in the geometric clustering for the chromosomes between the cell-types are a plausible factor leading to changes in cellular radiosensitivity. Furthermore, we investigate changes in cell shape, such as flattening, and show that this greatly impacts the distribution of DNA damage. This should be considered when comparing in vitro results to in vivo systems. The effect may be especially important when attempting to translate radiosensitivity measurements at the experimental in vitro level to the patient or human level.
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subjects Apoptosis
Biology and life sciences
Chromosome mapping
Chromosomes
Chromosomes - radiation effects
Cluster Analysis
Complications and side effects
Computer Simulation
Conformation
Crosslinking
Deoxyribonucleic acid
Distribution
DNA
DNA - radiation effects
DNA Breaks, Double-Stranded
DNA damage
DNA repair
DNA structure
Genome
Genomes
Geometry
Humans
Medicine and Health Sciences
Methods
Neoplasms - drug therapy
Physical Sciences
Polymers
Public health
Radiation
Radiation damage
Radiation effects
Radiation therapy
Radiation Tolerance
Radiotherapy
Simulation
Software
Space flight
Spatial distribution
Structural damage
Structure
Translocation
title Hi-C implementation of genome structure for in silico models of radiation-induced DNA damage
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