Intragenic regions that are removed during maturation of the RNA transcript—introns—are universally present in the nuclear genomes of eukaryotes1. The budding yeast, an otherwise intron-poor species, preserves two sets of ribosomal protein genes that differ primarily in their introns2,3. Although studies have shed light on the role of ribosomal protein introns under stress and starvation4,5,6, understanding the contribution of introns to ribosome regulation remains challenging. Here, by combining isogrowth profiling7 with single-cell protein measurements8, we show that introns can mediate inducible phenotypic heterogeneity that confers a clear fitness advantage. Osmotic stress leads to bimodal expression of the small ribosomal subunit protein Rps22B, which is mediated by an intron in the 5′ untranslated region of its transcript. The two resulting yeast subpopulations differ in their ability to cope with starvation. Low levels of Rps22B protein result in prolonged survival under sustained starvation, whereas high levels of Rps22B enable cells to grow faster after transient starvation. Furthermore, yeasts growing at high concentrations of sugar, similar to those in ripe grapes, exhibit bimodal expression of Rps22B when approaching the stationary phase. Differential intron-mediated regulation of ribosomal protein genes thus provides a way to diversify the population when starvation threatens in natural environments. Our findings reveal a role for introns in inducing phenotypic heterogeneity in changing environments, and suggest that duplicated ribosomal protein genes in yeast contribute to resolving the evolutionary conflict between precise expression control and environmental responsiveness9.
We thank the IST Austria Life Science Facility, the Miba Machine Shop and M. Lukačišinová for support with the liquid handling robot; the Bioimaging Facility at IST Austria, J. Power and B. Meier at the University of Cologne, and C. Göttlinger at the FACS Analysis Facility at the Institute for Genetics, University of Cologne, for support with flow cytometry experiments; L. Horst for the development of the automated experimental methods in Cologne; J. Parenteau, S. Abou Elela, G. Stormo, M. Springer and M. Schuldiner for providing us with yeast strains; B. Fernando, T. Fink, G. Ansmann and G. Chevreau for technical support; H. Köver, G. Tkačik, N. Barton, A. Angermayr and B. Kavčič for support during laboratory relocation; D. Siekhaus, M. Springer and all the members of the Bollenbach group for support and discussions; and K. Mitosch, M. Lukačišinová, G. Liti and A. de Luna for critical reading of our manuscript. This work was supported in part by an Austrian Science Fund (FWF) standalone grant P 27201-B22 (to T.B.), HFSP program Grant RGP0042/2013 (to T.B.), EU Marie Curie Career Integration Grant No. 303507, and German Research Foundation (DFG) Collaborative Research Centre (SFB) 1310 (to T.B.). A.E.-C. was supported by a Georg Forster fellowship from the Alexander von Humboldt Foundation.
Lukacisin M, Espinosa-Cantú A, Bollenbach MT. Intron-mediated induction of phenotypic heterogeneity. Nature. 2022. doi:10.1038/s41586-022-04633-0
Lukacisin, M., Espinosa-Cantú, A., & Bollenbach, M. T. (2022). Intron-mediated induction of phenotypic heterogeneity. Nature. Springer Nature. https://doi.org/10.1038/s41586-022-04633-0
Lukacisin, Martin, Adriana Espinosa-Cantú, and Mark Tobias Bollenbach. “Intron-Mediated Induction of Phenotypic Heterogeneity.” Nature. Springer Nature, 2022. https://doi.org/10.1038/s41586-022-04633-0.
M. Lukacisin, A. Espinosa-Cantú, and M. T. Bollenbach, “Intron-mediated induction of phenotypic heterogeneity,” Nature. Springer Nature, 2022.
Lukacisin M, Espinosa-Cantú A, Bollenbach MT. 2022. Intron-mediated induction of phenotypic heterogeneity. Nature.
Lukacisin, Martin, et al. “Intron-Mediated Induction of Phenotypic Heterogeneity.” Nature, Springer Nature, 2022, doi:10.1038/s41586-022-04633-0.