Research Highlight

Prof.dr. Matthias Heinemann

Using dynamic single-cell metabolite measurements, we found that metabolism of yeast is an autonomous oscillator[1], which under normal conditions operates in synchrony with the cell cycle, but can also orbit without cell cycle progression. Through solving a complex inverse problem, we obtained evidence that the metabolic oscillator controls both the early as well as the late cycle[2] (see illustration), offering a new view on how cell cycle control might be exerted. With dynamic microscopic analyses, we discovered that protein synthesis rate increases during the G1 phase, causing the levels of the early cyclin Cln3 to increase, which leads to the start of the cell cycle[3]. In our most recent work[4], we could show that key biosynthetic processes are temporally segregated along the cell cycle: protein biosynthesis activity has two waves per cell cycle, one in G1 and the other in S/G2/M, whereas the activities of lipid and polysaccharide biosynthesis synchronously peak only once in S/G2/M. We found that this unexpected temporal segregation in the biosynthetic processes is be responsible for the hour-scale oscillations in primary metabolism. Our next aims is now to understand how the identified temporal biosynthetic segregation is accomplished in terms of regulation to yield cell-cycle-autonomous oscillations, and with knowing this we then have everything in hand to investigate how the metabolic-biosynthetic oscillator mechanistically exerts cell cycle control[5].

[1] Papagiannakis A, et al. (2017) Autonomous metabolic oscillations robustly gate the early and late cell cycle. Molecular Cell 65: 285-295; DOI:https://doi.org/10.1016/j.molcel.2016.11.018

[2] Ozsezen S, et al. (2019) Inference of the high-level interaction topology between metabolic and cell-cycle oscillators from single-cell dynamics. Cell Systems 9: 354-365; DOI: 10.1016/j.cels.2019.09.003

[3] Litsios A, Huberts DHEW, Terpstra H, Guerra P, Schmidt A, Buczak K, Papagiannakis A, Rovetta M, Hekelaar J, Hubmann G, Exterkate M, Milias-Argeitis A & Heinemann M (2019) Differential scaling between G1 protein production and cell size dynamics promotes commitment to the cell division cycle in budding yeast, Nature Cell Biology, 21, 1382-1392

[4] Takhaveev V, Özsezen S, Smith EN, Zylstra A, Chaillet ML, Chen H, Papagiannakis A, Milias-Argeitis A & Heinemann M (2023) Temporal segregation of biosynthetic processes is responsible for metabolic oscillations during the budding yeast cell cycle, Nature Metabolism 5: 294–313.

[5] Current Opinion in Systems Biology (2022)