Division of Cancer Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, United Kingdom.
Christie Medical Physics and Engineering, The Christie NHS Foundation Trust, Manchester, United Kingdom.
PLoS Comput Biol. 2020 Dec 16;16(12):e1008476. doi: 10.1371/journal.pcbi.1008476. eCollection 2020 Dec.
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.
基因组组织领域的发展使得最近能够从实验测量的基因组接触（Hi-C 数据）中直接推断基因组的空间构象。这为染色体内和染色体间的排列提供了详细的描述。染色体混合是辐射诱导 DNA 错误修复的重要驱动因素。这是癌症治疗（放射治疗）、公共卫生（生物剂量测定）和太空旅行等领域的关键生物学终点。我们首次利用这些推断基因组组织的方法，并将其与纳米剂量辐射轨迹结构建模相结合，以预测特定细胞类型的几何形状内的 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，并受益于包含实验驱动的染色体构象。我们展示了 Hi-C 收缩图谱的变化如何影响推断的几何形状，导致染色体混合的显著差异。我们证明了这些差异如何传播到整个细胞核中 DNA 损伤分布的显著变化，这表明对 DNA 修复保真度和随后的细胞命运有影响。我们认为，细胞类型之间染色体的几何聚类差异是导致细胞辐射敏感性变化的一个合理因素。此外，我们研究了细胞形状的变化，如扁平化，并表明这极大地影响了 DNA 损伤的分布。在将体外结果与体内系统进行比较时，应考虑到这一点。当试图将实验体外水平的放射敏感性测量值转化为患者或人类水平时，这种影响可能尤其重要。
