Physics of Chromosomes

Extensile motor activity drives coherent motions in a model of interphase chromatin

The 3D spatiotemporal organization of the human genome inside the cell nucleus remains a major open question in cellular biology. In the time between two cell divisions, chromatin—the functional form of DNA in cells—fills the nucleus in its uncondensed polymeric form. Recent in vivo imaging experiments reveal that the chromatin moves coherently, having displacements with long-ranged correlations on the scale of micrometers and lasting for seconds.

To elucidate the mechanism(s) behind these motions, we develop a coarse-grained active polymer model where chromatin is represented as a confined flexible chain acted upon by molecular motors that drive fluid flows by exerting dipolar forces on the system. Numerical simulations of this model account for steric and hydrodynamic interactions as well as internal chain mechanics.

These demonstrate that coherent motions emerge in systems involving extensile dipoles and are accompanied by large-scale chain reconfigurations and nematic ordering. Comparisons with experiments show good qualitative agreement and support the hypothesis that self-organizing long-ranged hydrodynamic couplings between chromatin-associated active motor proteins are responsible for the observed coherent dynamics.

D. Saintillan, M. Shelley and A. Zidovska, Proc. Natl. Acad. Sci. USA, 115: 11442 (2018)

Chromatin Hydrodynamics
Following recent observations of large scale correlated motion of chromatin inside the nuclei of live differentiated cells, we present a hydrodynamic theory—the two-fluid model—in which the content of a nucleus is described as a chromatin solution with the nucleoplasm playing the role of the solvent and the chromatin fiber that of a solute.

This system is subject to both passive thermal fluctuations and active scalar and vector events that are associated with free energy consumption, such as ATP hydrolysis. Scalar events drive the longitudinal viscoelastic modes (where the chromatin fiber moves relative to the solvent) while vector events generate the transverse modes (where the chromatin fiber moves together with the solvent).

Using linear response methods, we derive explicit expressions for the response functions that connect the chromatin density and velocity correlation functions to the corresponding correlation functions of the active sources and the complex viscoelastic moduli of the chromatin solution. We then derive general expressions for the flow spectral density of the chromatin velocity field.

We use the theory to analyze experimental results recently obtained by one of the present authors and her co-workers. We find that the time dependence of the experimental data for both native and ATP-depleted chromatin can be well-fitted using a simple model—the Maxwell fluid—for the complex modulus, although there is some discrepancy in terms of the wavevector dependence.

Thermal fluctuations of ATP-depleted cells are predominantly longitudinal. ATP-active cells exhibit intense transverse long wavelength velocity fluctuations driven by force dipoles. Fluctuations with wavenumbers larger than a few inverse microns are dominated by concentration fluctuations with the same spectrum as thermal fluctuations but with increased intensity.

R. Bruinsma, A. Y. Grosberg, Y. Rabin and A. Zidovska, Biophys. J., 106: 1871 (2014)

The self-stirred genome: large-scale chromatin dynamics, its biophysical origins and implications

The organization and dynamics of the human genome govern all cellular processes — directly impacting the central dogma of biology — yet are poorly understood, especially at large length scales. Chromatin, the functional form of DNA in cells, undergoes frequent local remodeling and rearrangements to accommodate processes such as transcription, replication and DNA repair. How these local activities contribute to nucleus-wide coherent chromatin motion, where micron-scale regions of chromatin move together over several seconds, remains unclear. Activity of nuclear enzymes was found to drive the coherent chromatin dynamics, however, its biological nature and physical mechanism remain to be revealed. The coherent dynamics leads to a perpetual stirring of the genome, leading to collective gene dynamics over microns and seconds, thus likely contributing to local and global gene-expression patterns. Hence, a possible biological role of chromatin coherence may involve gene regulation.

A. Zidovska, Curr. Opin. Genet. Dev., 61: 83-90 (2020)

Micron-scale coherence in interphase chromatin dynamics

Chromatin structure and dynamics control all aspects of DNA biology yet are poorly understood, especially at large length scales. We developed an approach, displacement correlation spectroscopy (DCS) based on time-resolved image correlation analysis, to map chromatin dynamics simultaneously across the whole interphase nucleus in cultured human cells.

This method revealed that chromatin movement was coherent across large regions (4–5 μm) for several seconds. Regions of coherent motion extended beyond the boundaries of single-chromosome territories, suggesting elastic coupling of motion over length scales much larger than those of genes. These large-scale, coupled motions were ATP-dependent and unidirectional for several seconds, perhaps accounting for ATP- dependent directed movement of single genes.

This method revealed that chromatin movement was coherent across large regions (4–5 μm) for several seconds. Regions of coherent motion extended beyond the boundaries of single-chromosome territories, suggesting elastic coupling of motion over length scales much larger than those of genes. These large-scale, coupled motions were ATP-dependent and unidirectional for several seconds, perhaps accounting for ATP- dependent directed movement of single genes.

Perturbation of major nuclear ATPases such as DNA polymerase, RNA polymerase II, and topoisomerase II eliminated micron-scale coherence, while causing rapid, local movement to increase; i. e. , local motions accelerated but became uncoupled from their neighbors. We observe similar trends in chromatin dynamics upon inducing a direct DNA damage; thus we hypothesize that this may be due to DNA damage responses that physically relax chromatin and block long-distance communication of forces.

A. Zidovska, D. A. Weitz and T. J. Mitchison, Proc. Natl. Acad. Sci. USA, 110: 15555 (2013)

Interphase Chromatin Undergoes a Local Sol-Gel Transition upon Cell Differentiation

Cell differentiation, the process by which stem cells become specialized cells, is associated with chromatin reorganization inside the cell nucleus. Here, we measure the chromatin distribution and dynamics in embryonic stem cells in vivo before and after differentiation. We find that undifferentiated chromatin is less compact, more homogeneous, and more dynamic than differentiated chromatin.

Furthermore, we present a noninvasive rheological analysis using intrinsic chromatin dynamics, which reveals that undifferentiated chromatin behaves like a Maxwell fluid, while differentiated chromatin shows a coexistence of fluidlike (sol) and solidlike (gel) phases. Our data suggest that chromatin undergoes a local sol-gel transition upon cell differentiation, corresponding to the formation of the more dense and transcriptionally inactive heterochromatin.

I. Eshghi, J.A. Eaton and A. Zidovska, Phys. Rev. Lett., 126: 228101 (2021)