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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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Autores principales: Ingram, Samuel P., Henthorn, Nicholas T., Warmenhoven, John W., Kirkby, Norman F., Mackay, Ranald I., Kirkby, Karen J., Merchant, Michael J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7773326/
https://www.ncbi.nlm.nih.gov/pubmed/33326415
http://dx.doi.org/10.1371/journal.pcbi.1008476
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author Ingram, Samuel P.
Henthorn, Nicholas T.
Warmenhoven, John W.
Kirkby, Norman F.
Mackay, Ranald I.
Kirkby, Karen J.
Merchant, Michael J.
author_facet Ingram, Samuel P.
Henthorn, Nicholas T.
Warmenhoven, John W.
Kirkby, Norman F.
Mackay, Ranald I.
Kirkby, Karen J.
Merchant, Michael J.
author_sort Ingram, Samuel P.
collection PubMed
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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spelling pubmed-77733262021-01-07 Hi-C implementation of genome structure for in silico models of radiation-induced DNA damage Ingram, Samuel P. Henthorn, Nicholas T. Warmenhoven, John W. Kirkby, Norman F. Mackay, Ranald I. Kirkby, Karen J. Merchant, Michael J. PLoS Comput Biol Research Article 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. Public Library of Science 2020-12-16 /pmc/articles/PMC7773326/ /pubmed/33326415 http://dx.doi.org/10.1371/journal.pcbi.1008476 Text en © 2020 Ingram et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Ingram, Samuel P.
Henthorn, Nicholas T.
Warmenhoven, John W.
Kirkby, Norman F.
Mackay, Ranald I.
Kirkby, Karen J.
Merchant, Michael J.
Hi-C implementation of genome structure for in silico models of radiation-induced DNA damage
title Hi-C implementation of genome structure for in silico models of radiation-induced DNA damage
title_full Hi-C implementation of genome structure for in silico models of radiation-induced DNA damage
title_fullStr Hi-C implementation of genome structure for in silico models of radiation-induced DNA damage
title_full_unstemmed Hi-C implementation of genome structure for in silico models of radiation-induced DNA damage
title_short Hi-C implementation of genome structure for in silico models of radiation-induced DNA damage
title_sort hi-c implementation of genome structure for in silico models of radiation-induced dna damage
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7773326/
https://www.ncbi.nlm.nih.gov/pubmed/33326415
http://dx.doi.org/10.1371/journal.pcbi.1008476
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