Computer model of the human nucleus for structural and dynamical characterizations.

(A) 3D rendering of the nucleus model with particle-based representations for the 46 chromosomes shown as ribbons, the nuclear lamina (grey), nucleoli (cyan), and speckles (yellow). As shown on the right, chromosomes are modeled as beads-on-a- string polymers at a 100 KB resolution, with the beads further categorized into compartment A (red), compartment B (light blue), or centromeric regions (green). (B) Speckle particles undergo chemical modifications concurrent to their spatial dynamics, and the dephosphorylated (dP) particles contribute to droplet formation. (C) Illustration of the ideal and compartment potential that promotes chromosome compaction and microphase separation. Specific interactions between chromosomes and nuclear landmarks are shown on the right.

Overview of the iterative algorithm for parameterizing the nucleus model with experimental data.

Starting from an initial set of parameters, we perform MD simulations to produce an ensemble of nuclear structures. These structures can be transformed into contacts between chromosomes or between chromosomes and nuclear land- marks for direct comparison with experimental data. Differences between simulated and experiment contacts are used to update parameters for additional rounds of optimization if needed.

OpenNucleome facilitates GPU-accelerated simulations of the human nucleus.

(A) Illustration of workflow for setting up, performing, and analyzing MD simulations. (B) Python scripts setting up whole nucleus simulations. (C) Performance of MD simulations on different number of CPU cores and a single GPU.

Simulated structures reproduce contact frequencies between chromosomes and between chromosomes and nuclear landmarks.

(A) Comparison between simulated (top right) and experimental (bottom left) whole-genome contact probability maps. Zoom-ins of various regions are provided in Fig. S2. (B) Comparison between simulated and experimental average contact frequencies, including average contacts between genomic loci from the same chromosomes at a given separation (top), average contacts between genomic loci classified into different compartment types (middle), and average contacts between various chromosome pairs (bottom). (C) Comparison between simulated and experimental Lamin-B DamID (top) and SON TSA-Seq signals (bottom), with Pearson correlation coefficients of haploid chromosomes shown on the right.

Structural and dynamical predictions of the nucleus model match results from microscopy imaging.

(A) Comparison between the simulated and experimental radius of gyration, Rg, for haploid chromosomes. The Pearson correlation coefficient between the two, r, is shown in the legend. (B) Comparison between the simulated and experimental chromosome radial positions for haploid chromosomes, with their Pearson correlation coefficient shown in the legend. (B) Mean-squared displacements, MSDs, as a function of time are shown for selected telomeres. (B) The probability distribution of the anomalous exponent, α, obtained from fitting the MSDs curves with the expression, ⟨r2(Δt)⟩ = DαΔtα.

Heterogeneity and conserved features of nuclear organizations.

(A) Chromosome radial positions as a function of simulation time. (B) Contacts between chromosome 1 and 2 from two independent simulation trajectories show significant variations. (C) Genome-wide in silico Lamin B DamID (top) and SON TSA-Seq (bottom) profiles computed from two independent trajectories. Pearson correlation coefficients, r, are provided on each plot. (D) Pairwise Person correlation coefficients between interchromosomal contact matrices (left), genome-wide Lamin B DamID profiles (middle), and genome-wide SON TSA-Seq profiles (right) determined from independent trajectories. The averages excluding the diagonals of the three datasets are 0.06, 0.53, and 0.72.

Nuclear deformations influence genome organization while preserving chromatin-speckle contacts.

(A) Illustration of force induced nuclear envelope deformation. The nuclear lamina is modeled as a particle mesh where neighboring lamina particles are covalently bonded together. (B) Example nucleus conformations at different strengths of applied force. (C) Pearson correlation coefficients between results from simulations of deformed nuclei and those from a spherical nucleus for interchromosomal contacts (left), DamID profiles (middle), and TSA-Seq (right). The values at zero force were computed from two independent simulations starting from the same initial configurations.