Centromeres and telomeres as rheological probes of the human cell nucleus

The human genome contains genetic information essential for life, controlling all cellular processes via the central dogma of biology. It is a canonical example of a living polymer, yet the physical principles underlying its dynamical self-organization in the cell nucleus remain unknown. In this work, we investigate the polymeric nature of the genome in live human cells, by studying motions of the centers and free ends of linear chromosome polymers-the centromeres and telomeres-and rheology of their nuclear environment. Our findings reveal that telomeres have 10-times larger displacements than centromeres, exceeding by far predictions of polymer theories. We find that this unexpectedly large difference arises due to centromere and telomere localization in unique nuclear environments, distinct in both their biological activity and material rheology. While the former resides in the genome's silenced parts, the latter localizes in its transcriptionally active parts. Our rheological analysis shows that centromeres are embedded in an elastic environment, whereas telomeres' surroundings are viscous, directly affecting timescales and length scales of their respective motions. Our results suggest a key role of nuclear heterogeneity in genome dynamics, which we corroborate by biochemical perturbations of nuclear structures such as heterochromatin and nuclear speckles. Finally, upon homogenizing the nuclear environment by a hypoosmotic shock, we observe equal centromeric and telomeric motions, confirming our hypothesis. Our observations show that the heterogeneity of nuclear environment directly impacts timescales and length scales of local genomic motions, which may affect the spatiotemporal gene regulation across the cell nucleus.