How does cell size influence cellular biosynthesis and function?

A fundamental feature of cellular growth is that global protein and mRNA amounts scale with cell size. This ensures constant concentrations of key enzymes and reactants for the biochemical reactions that underpin core cellular processes. The precise scaling of mRNA content with cell size is achieved by two mechanisms: increased transcription due to limiting RNAPII and feedback on mRNA decay to stabilise transcripts in larger cells. However, this size-scaling of biosynthesis is only sustained within a limited size range; above which mRNA concentrations decrease, the cytoplasm becomes diluted, and many aspects of cellular physiology decline – including stem cells’ capacity to self-renew. I propose to elucidate the molecular mechanisms responsible for these size-dependent changes by identifying the mechanism for size-dependent mRNA decay feedback (Aim 1) and determining the molecular events responsible for the upper cell size limit for efficient biosynthesis (Aim 2). We will also address the open question of how cellular physiology is impacted by extreme small cell size (Aim 3). Initially using yeast as a model system, this will combine quantitative genomics, proteomics, and imaging. Molecular insights from yeast will then be tested in embryonic stem cells to determine how size impacts stem cell function (Aim 4).