Cell size, a complex trait at the crossroad between metabolism and the cell cycle – Deep-in-Size

Because yeast is highly amenable to genetics, our first objective can be as ambitious as to study the epistasis relationships among 400 mutants in order to systematically identify the pathways involved in cell size control.Our second objective is to characterize individually the function of each cell size control pathway and further, to decipher the intricate interconnections among all the cell size regulating routes. Because cell size is at the crossroad between metabolism and the regulation of cell cycle progression, we will combine cell biology, transcriptomics and metabolomics approaches to determine how each pathway affects cell size. This should lead to the identification of cell-size-specific transcriptional and metabolic signatures. Ultimately, this work should provide the bases to propose predictive and experimentally challengeable models of cell size regulation in a eukaryotic organism. Finally, we will explore the puzzling relationship between cell size and ageing. This original aspect of our project should lead to important conclusions on how these two major biological phenomena are interconnected at the molecular level.

in progress

in progress

in progress

Cell size can vary more than fifty folds among cell types and organisms, however for a given cell type, cell size is noticeably constant. Cell size homeostasis implies that specific mechanisms are devoted to estimating cell size and coordinating growth (increase in cell volume) and proliferation (increase in cell number).
Genome wide searches for yeast mutants affected for cell volume homeostasis have revealed that the inactivation of a myriad of genes can influence cell size. Indeed, about 500 knock-out mutants (8% of yeast genes) lead to a median cell volume diverging by more than 10% from the isogenic wild-type. This work also confirmed the central role of ribosome biogenesis in cell size control and interestingly pointed to the involvement of general nutrient sensing pathways (RAS, TOR) in this process, mainly via their downstream effectors (Sch9p, Sfp1p). In fact, epistasis studies have suggested that these general nutritional sensing cascades may affect cell size control through different means. Therefore, it is becoming clear that cell size control is not a simple linear route but is rather the result of an intricate network of interactions. Importantly, the vast majority of the cell-size mutants have not been positioned into defined signalling pathways. The cell size control process is thus a very interesting situation where multiple loci contributing to a complex quantitative trait have been identified but their organisation into separated pathways and respective influence remain to be elucidated.
The first objective of our project is to position the known ~400 most extreme cell-size mutants in distinct pathways by using a large-scale epistasis approach. This is possible due to the development of highly efficient genetic approaches in yeast. Then representatives of each pathway will be carefully characterized according to cell cycle progression, gene expression profile and metabolome. This will allow determining how each pathway intimately contributes to cell size homeostasis and hopefully identify specific transcriptomics or metabolic signatures. Finally, because both cell size and ageing are noticeably affected by nutrient availability and by inactivation of the same specific genes, the connection between cell size and ageing will be directly addressed. We believe that this systems-biology project will provide a clear view on how a large set of genes contribute to a highly complex quantitative trait.