核心概念
The computational model OpenNucleome enables high-resolution simulations of the human nucleus, uncovering insights into the mechanisms driving nuclear organization and the robustness of chromosome-nuclear body contacts.
要約
The content presents an open-source computational framework called OpenNucleome that enables high-resolution molecular dynamics simulations of the human nucleus. Key highlights:
The model represents the nucleus at a 100 KB resolution, including particle-based representations of chromosomes, nucleoli, nuclear speckles, and the nuclear lamina. This high-resolution allows for detailed structural and dynamical characterizations.
The model is designed based on a coupled self-assembly mechanism, where chromosomes, nuclear bodies, and their interactions are all accounted for. This approach enables the model to faithfully reproduce a diverse range of experimental data, including Hi-C, Lamin B DamID, and TSA-Seq profiles.
Implementing the model in the GPU-accelerated OpenMM framework enables efficient long-timescale simulations, providing insights into the dynamics of nuclear organization.
The simulations reveal significant heterogeneity in chromosome positions and interchromosomal contacts across individual cells, challenging the notion of robust radial positioning for gene regulation.
Despite this heterogeneity, the model predicts the existence of "fixed points" where specific genomic loci robustly maintain contacts with nuclear bodies like speckles. This supports a nuclear zoning model for genome function, where the anchoring of loci to nuclear landmarks creates stable molecular environments.
Further simulations demonstrate that nuclear deformation influences chromosome organization, but the contacts between chromosomes and nuclear bodies remain resilient, highlighting the importance of these conserved interactions.
Overall, the OpenNucleome framework provides a powerful tool for investigating the structural and dynamical aspects of nuclear organization, complementing experimental techniques and advancing our understanding of genome function.
統計
The average contact frequencies between genomic loci from the same chromosomes decay with sequence separation in a manner that matches experimental Hi-C data.
The average contact probabilities between different chromosome compartments (A, B, C) and between different chromosome pairs agree well with Hi-C measurements.
The simulated Lamin B DamID and SON TSA-Seq profiles closely match the corresponding experimental data.
The simulated radius of gyration and normalized radial positions of individual chromosomes agree with DNA-MERFISH measurements.
The anomalous subdiffusive motion of telomeres, characterized by the exponent α ≈ 0.59, matches experimental observations.
引用
"Notably, the simulated average contact probabilities between various compartment types match values estimated from Hi-C data."
"The simulated and experimental average contact probabilities between pairs of chromosomes agree well, and the Pearson correlation coefficient between the two datasets reaches 0.89."
"Remarkably, we found that chromosomes appear arrested and no significant changes in their positions are observed over timescales comparable to the cell cycle."