Transcriptomic balance and optimal growth are determined by cell size

Cell size and growth are intimately related across the evolutionary scale, but whether cell size is important to attain maximal growth or fitness is still an open question. We show that growth rate is a non-monotonic function of cell volume, with maximal values around the critical size of wild-type yeast cells. The transcriptome of yeast and mouse cells undergoes a relative inversion in response to cell size, which we associate theoretically and experimentally with the necessary genome-wide diversity in RNA polymerase II affinity for promoters. Although highly expressed genes impose strong negative effects on fitness when the DNA/mass ratio is reduced, transcriptomic alterations mimicking the relative inversion by cell size strongly restrain cell growth. In all, our data indicate that cells set the critical size to obtain a properly balanced transcriptome and, as a result, maximize growth and fitness during proliferation. [Display omitted] •Growth is a non-monotonic function that reaches a maximum around the critical size•The transcriptome of yeast and mouse cells becomes relatively inverted by cell size•Enforcing comparable transcriptomic inversions strongly restrains cell growth•Differential PIC binding to promoters explains the relative inversion by cell size Although most cells maintain their size within limits, the underlying reasons are uncertain. Comparing cells smaller or larger than normal, Vidal et al. find that size imposes a strong imbalance in the transcriptional machinery relative to the genome that, in turn, leads to profound gene expression and cell growth defects.