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Hi-C implementation of genome structure for in silico models of radiation-induced DNA damage
PLOS Computational Biology ( IF 4.3 ) Pub Date : 2020-12-16 , DOI: 10.1371/journal.pcbi.1008476
Samuel P. Ingram , Nicholas T. Henthorn , John W. Warmenhoven , Norman F. Kirkby , Ranald I. Mackay , Karen J. Kirkby , Michael J. Merchant

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 are 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.



中文翻译:

辐射诱导DNA损伤计算机模型的基因组结构的Hi-C实现

基因组组织领域的发展导致了最新的方法,可直接从实验测量的基因组接触(Hi-C数据)推断基因组的空间构象。这提供了染色体内和染色体间排列的详细描述。染色体混合是辐射诱导的DNA错修复的重要驱动力。这是与癌症治疗(放射疗法),公共卫生(生物剂量测定)和太空旅行等领域相关的关键生物学终点。首次,我们利用这些推断基因组组织的方法,并将其与纳米剂量辐射径迹结构建模相结合,以预测特定类型细胞内DNA损伤的数量和分布。这些纳米剂量模拟高度依赖于几何形状,并且受益于包含实验驱动的染色体构象。我们展示了Hi-C合同图的变化如何影响推断的几何结构,从而导致染色体混合中的显着差异。我们展示了这些差异如何传播到整个细胞核中DNA损伤分布的显着变化,这暗示了DNA修复保真度和后续细胞命运的意义。我们建议细胞类型之间染色体的几何簇的差异是导致细胞放射敏感性变化的合理因素。此外,我们研究了细胞形状的变化,例如变平,并表明这极大地影响了DNA损伤的分布。体外结果到体内系统。当尝试将体外实验水平的放射敏感性测量结果转换为患者或人类水平时,该效果可能尤其重要。

更新日期:2020-12-17
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