High-Resolution Computational Modeling of the Human Nucleus Reveals Insights into Genome Organization and Dynamics

Keskeiset käsitteet

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.

Tiivistelmä

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.

Tilastot

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.

Lainaukset

"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."

Tärkeimmät oivallukset

OpenNucleome for high resolution nuclear structural and dynamical modeling

by Lao,Z., Kama... klo www.biorxiv.org 10-18-2023

https://www.biorxiv.org/content/10.1101/2023.10.16.562451v2

Syvällisempiä Kysymyksiä

How can the OpenNucleome framework be extended to investigate the role of nuclear organization in gene regulation and cellular differentiation

The OpenNucleome framework can be extended to investigate the role of nuclear organization in gene regulation and cellular differentiation by incorporating additional features and functionalities.

Dynamic Gene Regulation: Introduce dynamic gene expression models that interact with the 3D genome structure to simulate gene regulation processes accurately. This can involve incorporating transcription factor binding, enhancer-promoter interactions, and chromatin looping dynamics.

Cellular Differentiation: Implement differentiation algorithms that mimic the changes in nuclear organization during cell fate determination. By simulating the reorganization of chromatin domains and nuclear bodies during differentiation, the framework can provide insights into the mechanisms underlying cell identity transitions.

Epigenetic Modifications: Include modules for modeling epigenetic modifications and their impact on chromatin structure and gene expression. This can help in studying how changes in histone modifications and DNA methylation patterns influence nuclear organization and cellular function.

Integration with Single-Cell Data: Incorporate features to analyze and integrate single-cell genomics data, such as single-cell Hi-C and single-cell RNA-seq, to study the heterogeneity in nuclear organization across individual cells and its implications for gene regulation.

Multi-Scale Modeling: Develop multi-scale modeling approaches that combine detailed chromatin structure simulations with higher-level cellular processes to understand how nuclear organization influences larger-scale cellular functions like cell division, signaling, and response to external stimuli.

By expanding the capabilities of OpenNucleome in these directions, researchers can gain a comprehensive understanding of the intricate relationship between nuclear organization, gene regulation, and cellular differentiation.

What are the potential limitations of the coupled self-assembly mechanism used in the model, and how could alternative modeling approaches provide additional insights

The coupled self-assembly mechanism used in the model may have potential limitations that could be addressed through alternative modeling approaches:

Limitation of Specific Interactions: The model's reliance on specific interactions for chromosome-nuclear body contacts may oversimplify the complexity of molecular interactions in the nucleus. Alternative approaches could incorporate more diverse and context-dependent interaction rules to capture the full spectrum of chromatin-nuclear body associations.

Dynamic Modeling: The current model may lack dynamic aspects of chromatin organization, such as active processes like loop extrusion or transcriptional activity. Alternative models could integrate dynamic processes to better simulate the real-time changes in nuclear organization and gene expression.

Incorporating Spatial Constraints: The model may not fully account for spatial constraints and physical forces that influence chromatin folding and nuclear organization. Alternative approaches could include physical constraints derived from experimental data or biophysical principles to enhance the accuracy of the simulations.

Integration of Signaling Pathways: To capture the influence of signaling pathways and external cues on nuclear organization, alternative modeling approaches could incorporate signaling cascades and regulatory networks that modulate chromatin structure and gene expression in response to environmental stimuli.

By exploring alternative modeling strategies that address these limitations, researchers can enhance the fidelity and predictive power of the model in elucidating the complex mechanisms governing nuclear organization and gene regulation.

Given the predicted resilience of chromosome-nuclear body contacts, how might this contribute to the maintenance of cellular identity and function in the face of stochastic changes in nuclear shape and chromosome positions

The predicted resilience of chromosome-nuclear body contacts can contribute significantly to the maintenance of cellular identity and function in the face of stochastic changes in nuclear shape and chromosome positions through several mechanisms:

Functional Stability: By anchoring specific genomic loci to nuclear bodies, the model suggests a mechanism for maintaining functional stability even in the presence of fluctuations in nuclear shape and chromosome positions. This anchoring ensures that critical gene regulatory elements remain in close proximity to essential nuclear structures for efficient gene expression.

Cellular Identity: The robust contacts between chromosomes and nuclear bodies can help preserve cellular identity by ensuring consistent spatial relationships between genomic regions and functional nuclear compartments. This stability in chromatin-nuclear body interactions may contribute to the maintenance of cell type-specific gene expression patterns.

Genome Functionality: The establishment of fixed points within the nucleus, as indicated by resilient chromosome-nuclear body contacts, supports the nuclear zoning model for genome functionality. This model suggests that specific genomic loci are spatially organized near nuclear bodies to create functional zones that regulate gene expression and chromatin dynamics.

Adaptation to Environmental Changes: The maintenance of stable chromosome-nuclear body contacts can enable cells to adapt to environmental changes or cellular stress by preserving essential genomic interactions. This resilience may help cells maintain proper gene regulation and cellular function under varying conditions.

Overall, the robustness of chromosome-nuclear body contacts in the model highlights a critical aspect of nuclear organization that contributes to the stability, functionality, and identity of cells in response to dynamic changes in their nuclear environment.