Scaling of Transcript Abundance with Cell Size and the Commitment to Cell Division

Project Summary/Abstract All cells must grow to a minimum size—the “critical size”—before they can commit to cell division. This size requirement prevents cells from becoming too big or small, and co-ordinates division with cell growth in mass. As a consequence of size control, cells have narrow and characteristic distributions of cell size—that is, size homeostasis. Despite decades of study, it is unknown how cells measure and respond to size, or why mechanistically a minimum size is required for commitment to division. The first term of this grant showed that as yeast cells grow in size, hundreds of mRNAs are systematically expressed at higher and higher levels—they increase in abundance faster than the increase in cell size, and so they increase in concentration. This is termed “super-scaling”. Other mRNAs do the opposite—they increase slower than the increase in size, and decrease in concentration—termed “sub-scaling”. Strikingly, genes that activate the cell cycle fall into the first group, while genes that inhibit the cell cycle fall into the second group. This immediately suggests a “Scaling” model for cell size control and homeostasis: the ratio of activators to inhibitors increases as G1 phase cells grow, and at a sufficiently high concentration of activators, inhibitors are overcome, and cells commit to division. The “sizer” that controls cell size is the mechanism that produces differential scaling of gene expression. Here, key aspects of this idea will be tested. A system will be developed for accurately measuring scaling of gene expression. A system will be developed for accurately measuring the variation in cell size at commitment to division. Most importantly, these newly- developed assays will be used to test several hypotheses for the mechanism by which genes are differentially expressed with size. The generality of the “Scaling” model will be addressed. Finally, the possibility that scaling is also occurring at the level of translation will be considered.