Cell size is tightly controlled in healthy tissues and single-celled organisms, but it remains unclear how cell size influences physiology. Increasing cell size was recently shown to remodel the proteomes of cultured human cells, demonstrating that large and small cells of the same type can be compositionally different. In the present study, we utilize the natural heterogeneity of hepatocyte ploidy and yeast genetics to establish that the ploidy-to-cell size ratio is a highly conserved determinant of proteome composition. In both mammalian and yeast cells, genome dilution by cell growth elicits a starvation-like phenotype, suggesting that growth in large cells is restricted by genome concentration in a manner that mimics a limiting nutrient. Moreover, genome dilution explains some proteomic changes ascribed to yeast aging. Overall, our data indicate that genome concentration drives changes in cell composition independently of external environmental cues.

健康组织和单细胞生物体的细胞大小受到严格控制，但目前尚不清楚细胞大小如何影响生理机能。最近证明，增加细胞大小可以重塑培养的人类细胞的蛋白质组，表明相同类型的大细胞和小细胞在组成上可能不同。在本研究中，我们利用肝细胞倍性和酵母遗传学的天然异质性来确定倍性与细胞大小之比是蛋白质组组成的高度保守的决定因素。在哺乳动物和酵母细胞中，细胞生长对基因组的稀释会引发饥饿样表型，这表明大细胞的生长受到基因组浓度的限制，其方式类似于限制性营养素。此外，基因组稀释解释了归因于酵母老化的一些蛋白质组学变化。总体而言，我们的数据表明，基因组浓度独立于外部环境线索驱动细胞组成的变化。