State Key Laboratory of Nuclear Physics and Technology, School of Physics, Peking University, Beijing, 100871, China.
Radiation Biology Center, Graduate School of Biostudies, Kyoto University, Kyoto, 606-8501, Japan.
Sci China Life Sci. 2020 Jun;63(6):825-834. doi: 10.1007/s11427-019-1638-6. Epub 2020 Apr 2.
Spatial chromatin structure plays fundamental roles in many vital biological processes including DNA replication, transcription, damage and repair. However, the current understanding of the secondary structure of chromatin formed by local nucleosome-nucleosome interactions remains controversial, especially for the existence and conformation of 30 nm structure. Since chromatin structure influences the fragment length distribution (FLD) of ionizing radiation-induced DNA strand breaks, a 3D chromatin model fitting FLD patterns can help to distinguish different models of chromatin structure. Here, we developed a novel "30-C" model combining 30 nm chromatin structure models with Hi-C data, which measured the spatial contact frequency between different loci in the genome. We first reconstructed the 3D coordinates of the 25 kb bins from Hi-C heatmaps. Within the 25 kb bins, lower level chromatin structures supported by recent studies were filled. Simulated FLD patterns based on the 30-C model were compared to published FLD patterns induced by heavy ion radiation to validate the models. Importantly, the 30-C model predicted that the most probable chromatin fiber structure for human interphase fibroblasts in vivo was 45% zig-zag 30 nm fibers and 55% 10 nm fibers.
空间染色质结构在许多重要的生物学过程中起着基本作用，包括 DNA 复制、转录、损伤和修复。然而，目前对于局部核小体-核小体相互作用形成的染色质二级结构的理解仍存在争议，特别是对于 30nm 结构的存在和构象。由于染色质结构会影响电离辐射诱导的 DNA 链断裂的片段长度分布（FLD），因此拟合 FLD 模式的 3D 染色质模型可以帮助区分不同的染色质结构模型。在这里，我们开发了一种新的“30-C”模型，该模型结合了 30nm 染色质结构模型和 Hi-C 数据，测量了基因组中不同基因座之间的空间接触频率。我们首先从 Hi-C 热图中重建了 25kb -bin 的 3D 坐标。在 25kb-bin 内，填充了最近研究支持的较低层次的染色质结构。基于 30-C 模型模拟的 FLD 模式与重离子辐射诱导的已发表的 FLD 模式进行了比较，以验证模型。重要的是，30-C 模型预测，体内人成纤维细胞间期最可能的染色质纤维结构是 45%的锯齿状 30nm 纤维和 55%的 10nm 纤维。
