Protein-driven colloid-osmotic pressure controls nuclear size, organization, and function

The size of the cell nucleus is tightly controlled and changes in nuclear size correlate with altered nuclear function during development, cell differentiation and senescence ^1–4 . How nuclear size is regulated ⁵ and whether changes thereof are functionally relevant remains unclear. Here, we demonstrate that nuclear size is determined by the osmotic pressure exerted by proteins in yeast, human cells and frog egg extracts. The biophysical model we establish solves the long-standing question of how the nuclear-to-cytoplasmic ratio is regulated and maintained ^6,7 . Furthermore, altering protein-driven osmotic balance modulates the physical properties of the nucleus, with a direct effect on chromatin organization and gene expression: Nuclear enlargement causes the dissolution of heterochromatic structures and derepression of subtelomeres and transposons, while simultaneously down-regulating highly expressed housekeeping genes. Importantly, these global transcriptional patterns closely mimic the gene expression changes that occur as yeast, human, and drosophila cells enlarge. Importantly, artificially forcing nuclear compression is sufficient to reverse these size-associated expression changes. Together, our findings provide a quantitative, mechanistic explanation for the coupling between the size of the nucleus and the cell, and they establish nuclear size as a modulator of chromatin organization and gene expression.