Simulation of Different Three-Dimensional Models of Whole Interphase Nuclei Compared to Experiments - A Consistent...

Area of Science:

• Computational biology and biophysics
• Genomics and molecular biology
• Cell biology and nuclear organization

Background:

• The three-dimensional (3D) organization, arrangement, and dynamics of chromosomes within cell nuclei are crucial for genome function but remain debated.
• Genome functions, including storage, replication, and transcription, are intricately linked with the dynamic 3D architecture of chromatin.

Purpose of the Study:

• To investigate how the 30 nm chromatin fiber organizes into chromosomes, including their arrangement and morphology, through whole nucleus simulations.
• To compare two distinct models, the Multi-Loop-Subcompartment (MLS) and Random-Walk/Giant-Loop (RW/GL) models, against experimental data.

Main Methods:

• A scale-bridging framework simulating the 30 nm chromatin fiber as a polymer chain with various interactions.
• Application of simulated annealing and Brownian Dynamics methods to generate interphase configurations from metaphase states.
• Comparison of simulation results with experimental data, including microscopy images and spatial distance measurements.

Main Results:

• Both MLS and RW/GL models formed chromosome territories, but the MLS model's rosettes produced distinct subchromosomal domains, aligning with experimental observations.
• The MLS model accurately predicted low overlap of chromosomes and subchromosomal domains, unlike the RW/GL model.
• Simulations favored an MLS-like model with specific loop and linker sizes (63–126 kbp), predicting large inter-fiber spaces that permit molecular diffusion, challenging the Interchromosomal Domain (ICD) hypothesis.

Conclusions:

• Polymer simulations strongly favor a stable loop aggregate/rosette genome architecture (MLS model) over other topologies.
• This genome architecture is tightly connected to the global morphology and dynamics of the cell nucleus, providing a framework for understanding genome organization.
• The findings support a novel framework for genome emergence, function, and evolution, with implications for diagnosis and treatment.