Chromatin compaction scaling with cell size follows a power law from interphase through mitosis.

Coordination of mitotic chromosome compaction with cell size is crucial for proper genome segregation during mitosis. During development, DNA content remains constant, but cell size changes dynamically, necessitating a mechanism that scales chromosome compaction with cell size to ensure proper chromatin segregation. In this study, we examined chromatin compaction in the developing Drosophila nervous system by analyzing the large neuronal stem cells and their smaller progeny, the ganglion mother cells. Using super-resolution 3D stochastic optical reconstruction microscopy and quantitative time-lapse fluorescence microscopy, we observed that nanoscale chromatin density during interphase scales with nuclear volume according to a power law. This scaling relationship is disrupted by inhibiting histone deacetylase activity, indicating that molecular cues rather than mechanical constraints primarily regulate chromatin compaction. Notably, this power law dependency is maintained into mitosis, but the scaling exponent decreases. This suggests a phase-separation-like transition in the biophysical state of chromatin, whereby the polymer shifts from a more expanded to a more compact configuration. Accordingly, we propose that the scaling of mitotic chromosome size relative to cell size emerges from the organizational principles of interphase chromatin, and that mitotic compaction may be governed by polymer properties modulated by changes in the chromatin-solvent environment.