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.
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)