RNA Methylation by the MIS Complex Regulates a Cell Fate Decision in Yeast

Abstract

For the yeast Saccharomyces cerevisiae, nutrient limitation is a key developmental signal causing diploid cells to switch from yeast-form budding to either foraging pseudohyphal (PH) growth or meiosis and sporulation. Prolonged starvation leads to lineage restriction, such that cells exiting meiotic prophase are committed to complete sporulation even if nutrients are restored. Here, we have identified an earlier commitment point in the starvation program. After this point, cells, returned to nutrient-rich medium, entered a form of synchronous PH development that was morphologically and genetically indistinguishable from starvation-induced PH growth. We show that lineage restriction during this time was, in part, dependent on the mRNA methyltransferase activity of Ime4, which played separable roles in meiotic induction and suppression of the PH program. Normal levels of meiotic mRNA methylation required the catalytic domain of Ime4, as well as two meiotic proteins, Mum2 and Slz1, which interacted and co-immunoprecipitated with Ime4. This MIS complex (Mum2, Ime4, and Slz1) functioned in both starvation pathways. Together, our results support the notion that the yeast starvation response is an extended process that progressively restricts cell fate and reveal a broad role of post-transcriptional RNA methylation in these decisions.

Author Summary

Cellular differentiation involves the limitation of cellular potential in response to developmental cues. Budding yeast cells differentiate in response to nutrient availability. In the presence of nutrients, cells divide mitotically by producing round, yeast-form buds. Under nutrient limitation, cells can either divide under a pseudo-hyphal (PH) foraging program or undergo meiosis to form protective spores. We show here that developmental commitment occurs in two distinct phases. When nutrients were removed, cells first became committed to a starvation response, during which they entered the meiotic program. If nutrient limitation persisted, cells became committed to meiosis and sporulation. By contrast, if nutrients were returned at this point, cells synchronously initiated PH foraging growth. We found that both sporulation and PH growth were governed by RNA methylation, and we identified an mRNA–methyltransferase complex comprising Mum2, Ime4, and Slz1 as a central regulator of these developmental trajectories. Our results indicate that the yeast starvation response is an extended developmental process and reveal a fundamental role for post-transcriptional RNA modification in controlling cell fate.