Transcriptomic balance and optimal growth are determined by cell size

Abstract

Cell size and growth are intimately related across the evolutionary scale, and the molecular pathways underlying cell size homeostasis have received much attention over the last decades. However, whether cell size is important to attain maximal growth or fitness is still an open question, and the reasons why a critical size is needed for triggering key transitions of the cell cycle are unknown. We show that growth is a non-monotonic function of volume in yeast cells, with maximal values around the critical size. Comparing small to normal, large and outsized cells, the transcriptome undergoes an extensive inversion that correlates with RNA polymerase II occupancy. Accordingly, highly expressed genes impose strong negative effects on growth when their DNA/mass ratio is altered. A similar transcriptomic inversion is displayed by mouse liver cells of different sizes, suggesting that the uncovered mechanistic implications of cell size on growth and fitness are universal. We propose that cell size is set to attain a properly balanced transcriptome and, hence, maximize growth during cell proliferation.