Department of Chemistry, Massachusetts Institute of Technology, Cambridge, United States.
Elife. 2024 Aug 15;13:RP93223. doi: 10.7554/eLife.93223.
The intricate structural organization of the human nucleus is fundamental to cellular function and gene regulation. Recent advancements in experimental techniques, including high-throughput sequencing and microscopy, have provided valuable insights into nuclear organization. Computational modeling has played significant roles in interpreting experimental observations by reconstructing high-resolution structural ensembles and uncovering organization principles. However, the absence of standardized modeling tools poses challenges for furthering nuclear investigations. We present OpenNucleome-an open-source software designed for conducting GPU-accelerated molecular dynamics simulations of the human nucleus. OpenNucleome offers particle-based representations of chromosomes at a resolution of 100 KB, encompassing nuclear lamina, nucleoli, and speckles. This software furnishes highly accurate structural models of nuclear architecture, affording the means for dynamic simulations of condensate formation, fusion, and exploration of non-equilibrium effects. We applied OpenNucleome to uncover the mechanisms driving the emergence of 'fixed points' within the nucleus-signifying genomic loci robustly anchored in proximity to specific nuclear bodies for functional purposes. This anchoring remains resilient even amidst significant fluctuations in chromosome radial positions and nuclear shapes within individual cells. Our findings lend support to a nuclear zoning model that elucidates genome functionality. We anticipate OpenNucleome to serve as a valuable tool for nuclear investigations, streamlining mechanistic explorations and enhancing the interpretation of experimental observations.
人类细胞核的复杂结构组织是细胞功能和基因调控的基础。最近，实验技术的进步，包括高通量测序和显微镜技术，为核组织提供了有价值的见解。计算建模通过重建高分辨率结构集合和揭示组织原则，在解释实验观察方面发挥了重要作用。然而，缺乏标准化的建模工具给进一步的核研究带来了挑战。我们提出了 OpenNucleome，这是一款用于进行人类细胞核的 GPU 加速分子动力学模拟的开源软件。OpenNucleome 提供了分辨率为 100KB 的染色体的基于粒子的表示，包括核纤层、核仁、斑点。该软件提供了高度精确的核结构模型，为凝聚态形成、融合以及探索非平衡效应的动力学模拟提供了手段。我们应用 OpenNucleome 来揭示驱动细胞核中“固定点”出现的机制，这些固定点表示基因组位点稳健地锚定在特定核体附近，以实现特定的功能目的。即使在单个细胞中染色体的径向位置和核形状发生显著波动的情况下，这种锚定仍然具有弹性。我们的研究结果支持核分区模型，该模型阐明了基因组的功能。我们预计 OpenNucleome 将成为核研究的有力工具，简化机制探索并增强对实验观察的解释。
