Nadal Ribelles, Mariona, 1984-Lieb, GuillaumeSolé, CarmeMatas, YaimaSzachnowski, UgoAndjus, SaraQuintana, MariaRomo, MònicaGonzalez Herrero, AitorMorillon, AntoninPelet, SergeNadal Clanchet, Eulàlia dePosas Garriga, Francesc2025-05-082025-05-082025Nadal-Ribelles M, Lieb G, Solé C, Matas Y, Szachnowski U, Andjus S, et al. Transcriptional heterogeneity shapes stress-adaptive responses in yeast. Nat Commun. 2025 Mar 17;16(1):2631. DOI: 10.1038/s41467-025-57911-62041-1723http://hdl.handle.net/10230/70329In 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.application/pdfeng© The Author(s) 2025. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.info:eu-repo/semantics/articlehttp://dx.doi.org/10.1038/s41467-025-57911-6Gene expressionRNATranscriptioninfo:eu-repo/semantics/openAccess