Nutrient-dependent histone homeostasis in budding yeast

• Applicant: Dr. Kurt Michael Schmoller
• Subject Area: Cell Biology
• Term: since 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 416098229

Cells need to accurately control protein concentrations according to cell state and external cues. To maintain constant concentrations during cell growth, the synthesis of many proteins is tightly coupled to cell volume through limiting transcriptional and translational machinery. By contrast, we have recently shown that histone amounts need to be coupled to genome content to maintain a constant histone-to-DNA stoichiometry. Using budding yeast as a model and genetic manipulation of cell volume, we have demonstrated that the coupling of histone amounts to genome content is already achieved at the transcript level and that histone promoters can be sufficient for this regulation. Based on our findings, we propose that in contrast to most genes, whose transcription is limited by the transcriptional machinery, transcription driven by histone promoters is limited by the template, i.e. the gene, instead.Here, I propose to extensively test the ‘template-limited transcription’ hypotheses for histone homeostasis in budding yeast and investigate how histone homeostasis is achieved in changing nutrient conditions, which not only cause a change in cell size, but also modulate growth rate and cell cycle distributions. The latter is particularly relevant for strongly cell-cycle-dependent genes such as histones, whose expression is temporally linked to DNA replication. A decrease in the relative duration of S-phase likely has to be compensated for by increased expression amplitude, yet how this is achieved is completely unclear. We will use a combination of live-cell microscopy, single molecule FISH, molecular biology approaches, and mathematical modeling to unravel the contributions of transcription, mRNA degradation and regulation at the protein level to histone homeostasis in different nutrients. Obtaining a quantitative understanding of how cells maintain constant histone-to-DNA stoichiometry despite changes in overall protein content will establish budding yeast histone homeostasis as a model system for molecular regulation of proteome allocation according to environmental conditions.

• DFG Programme: Research Grants