Transcriptional heterogeneity shapes stress-adaptive responses in yeast

Mariona Nadal-Ribelles (), Guillaume Lieb, Carme Solé, Yaima Matas, Ugo Szachnowski, Sara Andjus, Maria Quintana, Mònica Romo, Aitor Gonzalez Herrero, Antonin Morillon, Serge Pelet, Eulàlia Nadal () and Francesc Posas ()
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Mariona Nadal-Ribelles: Universitat Pompeu Fabra
Guillaume Lieb: University of Lausanne
Carme Solé: Universitat Pompeu Fabra
Yaima Matas: Universitat Pompeu Fabra
Ugo Szachnowski: F-75248
Sara Andjus: F-75248
Maria Quintana: Universitat Pompeu Fabra
Mònica Romo: Universitat Pompeu Fabra
Aitor Gonzalez Herrero: Universitat Pompeu Fabra
Antonin Morillon: F-75248
Serge Pelet: University of Lausanne
Eulàlia Nadal: Universitat Pompeu Fabra
Francesc Posas: Universitat Pompeu Fabra

Nature Communications, 2025, vol. 16, issue 1, 1-17

Abstract: Abstract In response to stress, cells activate signaling pathways that coordinate broad changes in gene expression to enhance cell survival. Remarkably, complex variations in gene expression occur even in isogenic populations and in response to similar signaling inputs. However, the molecular mechanisms underlying this variability and their influence on adaptive cell fate decisions are not fully understood. Here, we use scRNA-seq to longitudinally assess transcriptional dynamics during osmoadaptation in yeast. Our findings reveal highly heterogeneous expression of the osmoresponsive program, which organizes into combinatorial patterns that generate distinct cellular programs. The induction of these programs is favored by global transcriptome repression upon stress. Cells displaying basal expression of the osmoresponsive program are hyper-responsive and resistant to stress. Through a transcription-focused analysis of more than 300 RNA-barcoded deletion mutants, we identify genetic factors that shape the heterogeneity of the osmostress-induced transcriptome, define regulators of stress-related subpopulations and find a link between transcriptional heterogeneity and increased cell fitness. Our findings provide a regulatory map of the complex transcriptional phenotypes underlying osmoadaptation in yeast and highlight the importance of transcriptional heterogeneity in generating distinct adaptive strategies.

Date: 2025
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DOI: 10.1038/s41467-025-57911-6

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