DNA:cytoplasm ratio defines an upper limit to cell size [RNA-seq]

Cell size varies greatly between cell types, yet within a specific cell type and growth condition, cell size is narrowly distributed. Why maintenance of a cell-type specific cell size is important is not understood. Here we show that growing beyond a certain size has wide-ranging effects on cell physiology. Large cells are defective in gene induction, cell cycle progression and cell signaling. We further show that these defects are caused by the inability of large cells to scale nucleic acid and protein biosynthesis in accordance with cell volume increase, which effectively leads to cytoplasm dilution. Finally, we determine why nucleic acid and protein biosynthesis do not scale with cell volume beyond a certain critical size. DNA becomes limiting. We conclude that the correct DNA to cytoplasm ratio is vital for many perhaps all cellular functions and that the range where this ratio supports optimal cell function is remarkably narrow. Total RNA sequenced from fixed numbers of S. cerevisiae cells of varying size mixed with a fixed number exponentially growing C. albicans cells. The S. cerevisiae counts were normalized to total number of C.albicans reads in each sample.