Genome dilution by cell growth drives starvation-like proteome remodeling in mammalian and yeast cells

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. Here, we utilize the natural heterogeneity of hepatocyte ploidy and yeast genetics to establish that 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 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.在健康组织及单细胞生物体内，细胞大小受到严格调控，但目前仍未明确细胞大小如何影响机体生理状态。近期研究发现，增大细胞大小可重塑体外培养人类细胞的蛋白质组（proteome），证明同一类型细胞的大、小细胞在组分上存在显著差异。本研究借助肝细胞倍性（ploidy）的天然异质性与酵母遗传学技术，证实倍性与细胞大小的比值是决定蛋白质组组成的高度保守调控因子。在哺乳动物细胞与酵母细胞中，细胞生长引发的基因组稀释会诱导出类似饥饿的表型，这提示大细胞的生长会受到基因组浓度的限制，其机制模拟了营养供给受限的状态。此外，基因组稀释可解释部分归因于酵母衰老的蛋白质组变化。综上，本研究数据表明，基因组浓度可独立于外界环境信号，驱动细胞组分发生改变。