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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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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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.</description><identifier>ISSN: 1553-7358</identifier><identifier>ISSN: 1553-734X</identifier><identifier>EISSN: 1553-7358</identifier><identifier>DOI: 10.1371/journal.pcbi.1008476</identifier><identifier>PMID: 33326415</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>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</subject><ispartof>PLoS computational biology, 2020-12, Vol.16 (12), p.e1008476-e1008476</ispartof><rights>COPYRIGHT 2020 Public Library of Science</rights><rights>2020 Ingram et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. 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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. 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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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