Stochastic chromatin packing of 3D mitotic chromosomes revealed by coherent X-rays-猫眼课题宝

DOI：

10.1073/pnas.2109921118

发表时间：

2021-11

期刊：

Proceedings of the National Academy of Sciences

影响因子：

通讯作者：

中科院分区：

其他

文献类型：

作者：

Daeho Sung;Chan Lim;M. Takagi;C. Jung;Heemin Lee;D. Cho;Jaeyong Shin;Kangwoo Ahn;Junha Hwang;D. Nam;Y. Kohmura;Tetsuya Ishikawa;D. Noh;N. Imamoto;Jae-Hyung Jeon;Changyong Song

意义一米长的DNA分子和几微米大小的染色体之间的结构联系，以及它们高度空间有效和无故障的打包和解包机制仍然是一个谜。这项研究解决了这一基本问题，通过使用低温相干X射线衍射层析成像来解决人类染色体的三维结构。在冷冻水合条件下保存的中期染色体的结构，以及三维电子密度分布的定量细节，在纳米尺度上得到了。通过对三维结构的几何分析和统计建模，揭示了结构形成的本质是随机过程。在支持结构分析的同时，分子动力学模拟进一步阐明了染色质和DNA结合蛋白之间的短程吸引在形成微米大小的染色体中的关键作用。DNA分子是原子级的信息存储分子，通过复制和转录的无故障重复来促进可靠的信息传输。将几米长的DNA压缩成微米级物体的惊人精度，以及相反的情况，使染色体成为从物理和生物角度来看最有趣的结构之一。然而，它的三维(3D)结构仍然难以捉摸，在数十纳米分辨率下观察样品的自然结构方面存在挑战。在这里，利用低温相干X射线衍射成像，我们成功地获得了中期染色体的纳米级三维结构，该结构表现出电子密度的随机分布，而不具有高阶折叠结构的特征。对染色体的标度分析，与具有与实验结果相同的密度分布的模型结构相比较，发现了密度分布的分形性。经分子动力学模拟证实的定量三维密度图显示，染色体的内部结构符合扩散限制的聚集行为，这表明三维染色质堆积是通过随机过程发生的。

Significance The structural link between meter-long DNA molecules and chromosomes a few microns in size and their highly space-effective and fault-free packing and unpacking mechanisms remain a puzzle. This research addressed this fundamental issue by resolving a three-dimensional (3D) structure of human chromosomes using cryogenic coherent X-ray diffraction tomography. Structures of metaphase chromosomes, preserved in a frozen hydrated condition, with quantitative details on 3D electron density distributions were obtained at nanometer-scale resolution. The geometrical analysis of the 3D structures with the statistical modeling unveils that the stochastic process is the essence of the structure formation. While supporting the structural analysis, molecular dynamics simulations further elucidate the critical role of short-range attraction between chromatins and DNA-binding proteins in forming micrometer-sized chromosomes. DNA molecules are atomic-scale information storage molecules that promote reliable information transfer via fault-free repetitions of replications and transcriptions. Remarkable accuracy of compacting a few-meters-long DNA into a micrometer-scale object, and the reverse, makes the chromosome one of the most intriguing structures from both physical and biological viewpoints. However, its three-dimensional (3D) structure remains elusive with challenges in observing native structures of specimens at tens-of-nanometers resolution. Here, using cryogenic coherent X-ray diffraction imaging, we succeeded in obtaining nanoscale 3D structures of metaphase chromosomes that exhibited a random distribution of electron density without characteristics of high-order folding structures. Scaling analysis of the chromosomes, compared with a model structure having the same density profile as the experimental results, has discovered the fractal nature of density distributions. Quantitative 3D density maps, corroborated by molecular dynamics simulations, reveal that internal structures of chromosomes conform to diffusion-limited aggregation behavior, which indicates that 3D chromatin packing occurs via stochastic processes.

Stochastic chromatin packing of 3D mitotic chromosomes revealed by coherent X-rays

文献摘要

相似文献