Nuclear size is genetically controlled and influences cell fate

The proportional scaling between nuclear and cell size was first described more than 150 years ago and is among the most conserved features of cellular organization. Yet the mechanisms that establish this scaling and its physiological significance have remained unresolved. Here, we address both questions by combining image-enabled cell sorting with genome-wide CRISPR screening, transcriptomics and functional analyses. We identify more than 180 regulators of the nuclear-to-cell ratio and show that distinct classes of genes independently control nuclear and cell size. RNA metabolism predominantly regulates nuclear size, whereas protein synthesis and degradation primarily regulate cell size. This supports a model in which differences in macromolecular partitioning between the nucleus and cytoplasm contribute to osmotic regulation of nuclear size together with mechanical constraints imposed by chromatin, the cytoskeleton, and the nuclear envelope. Changes in nuclear size cause widespread transcriptional remodeling that is independent of changes in cell size. Cells with smaller nuclei exhibit reduced PRC2-dependent H3K27 trimethylation, activation of developmental gene-expression programmes and repression of cell-cycle genes. Consistent with these changes, mouse embryonic stem cells with smaller nuclei show an increased propensity to exit pluripotency and initiate differentiation in response to retinoic acid. Together, our findings provide a mechanistic framework for nuclear size scaling and establish nuclear size as a physical regulator of gene expression and cell-state transitions, linking cellular architecture to cell fate.