The interplay of chromatin phase separation and lamina interactions in nuclear organization

Abstract

The genetic material of eukaryotes is segregated into transcriptionally active euchromatin and silent heterochromatin compartments. The spatial arrangement of chromatin compartments evolves over the course of cellular life in a process that remains poorly understood. The latest nuclear imaging experiments reveal a number of dynamical signatures of chromatin that are reminiscent of active multiphase liquids. This includes the observations of viscoelastic response, coherent motions, Ostwald ripening, and coalescence of chromatin compartments. There is also growing evidence that liquid-liquid phase separation of protein and nucleic acid components is the underlying mechanism for the dynamical behavior of chromatin. To dissect the organizational and dynamical implications of chromatin's liquid behavior, we have devised a phenomenological field-theoretic model of the nucleus as a multiphase condensate of liquid chromatin types. Employing the liquid chromatin model of the Drosophila nucleus, we have carried out an extensive set of simulations with an objective to shed light on the dynamics and chromatin patterning observed in the latest nuclear imaging experiments. Our simulations reveal the emergence of experimentally detected mesoscale chromatin channels and spheroidal droplets which arise from the dynamic interplay of chromatin type to type interactions and intermingling of chromosomal territories. We also quantitatively reproduce coherent motions of chromatin domains observed in displacement correlation spectroscopy measurements which are explained within the framework of our model by phase separation of chromatin types operating within constrained intrachromosomal and interchromosomal boundaries. Finally, we illuminate the role of heterochromatin-lamina interactions in the nuclear organization by showing that these interactions enhance the mobility of euchromatin and indirectly introduce correlated motions of heterochromatin droplets.

Figure 1

Schematic representation of the mulitphase liquid chromatin model of nucleus. Shown are the key physical interactions that make up the global nuclear free energy functional. Namely, the chromosome territorial interactions (CTs), interactions between cHC and fHC types (cHC-cHC, cHC-fHC, and fHC-fHC) and the lamina interaction which is modeled via surface gradient terms modulated by ${\gamma }_1$ (cHC-lamina) and ${\gamma }_2$ (fHC-lamina). To see this figure in color, go online.

Figure 2

Compartmentalization patterns of nuclear chromatin. The snapshots show the emergence of chromatin compartmentalization at different time steps initiated with attractive and repulsive interactions between the cHC and fHC HC types. (A) Simulated structures obtained for attractive interaction between cHC-fHC with a weaker mixing affinity of cHC (top panel) and stronger mixing affinity (bottom panel). (B) Simulated structures obtained with repulsive interaction between cHC-fHC with a weaker mixing affinity of cHC HC (top panel) and stronger mixing affinity of cHC (bottom panel). The green color indicates the chromosome territories, while the blue and red colors indicate the HC types cHC and fHC regions, respectively. (C) Relaxation dynamics of chromosomal volume V, the cHC volume v, and fHC volume w. (D) Heterochromatin droplet heterogeneity quantified as area distribution as a function of simulated time. To see this figure in color, go online.

Figure 3

The role of HC mobility and fluctuations on the emergent subnuclear chromatin morphology and dynamics. (A) Shown are nuclear chromatin patterns for repulsive interaction between cHC and fHC HC types and weaker mixing affinity of both cHC and fHC. (B) Displacement fields of cHC and fHC corresponding to one-time units. Shown are simulation results from fast intermediate and slow diffusion coefficients corresponding to panels arranged from top to bottom, respectively. Colors correspond to cHC and fHC, respectively. (C) Calculated spatial correlation functions of displacement fields as a function of the displacement period. (D) Dynamic structure factors of HC domains. Shown are results from fast intermediate and slow diffusion coefficients corresponding to panels arranged from top to bottom, respectively. (E) Comparison of orientation displacement vectors from simulations (left panel) with the experimentally obtained spatial displacement autocorrelation functions from displacement correlation spectroscopy experiments (right panel) reported by Zidovska et al. (49). Arrows are colored by direction. (F) Reproduction of the figure of spatial displacement auto-correlation functions of in situ nuclear chromatin measured by displacement correlation spectroscopy as reported in Zidovska et al. (49). To see this figure in color, go online.

Figure 4

The role of lamina-HC interactions on nuclear chromatin patterns. (A) Shown are nuclear morphologies generated for various strengths of nuclear lamina interactions with cHC domain ${\gamma }_1$ and fHC domain ${\gamma }_2$. (B) Radially averaged density profile of cHC measured from a center of nucleus. (C) Radially averaged density profile of fHC measured from a center of nucleus. To see this figure in color, go online.

Figure 5

Variation of the average density of cHC and fHC HC types. (A) Shown are simulated nuclear chromatin patterns for different values of HC content fraction in the nucleus as a function of interactions strength between cHC-fHC domains. (B) Profiles of the phase-field variables ${\psi }_1$ and ${\psi }_2$ along the major-axis of the nucleus as a function of HC density. The profile plots are associated with the simulated morphology presented in (A) in the same order as the strength of the cHC-fHC interactions. To see this figure in color, go online.