A single-cell resolved genotype-phenotype map using genome-wide genetic and environmental perturbations

Heterogeneity is inherent to living organisms and it determines cell fate and phenotypic variability. Despite its ubiquity, the underlying molecular mechanisms and the genetic basis linking genotype to-phenotype heterogeneity remain a central challenge. Here we construct a yeast knockout library wit...

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Autores: Nadal Ribelles, Mariona, 1984-, Solé, Carme, Díez Villanueva, Pablo, Stephan-Otto Attolini, Camille, Matas, Yaima, Steinmetz, Lars M., Nadal Clanchet, Eulàlia de, Posas Garriga, Francesc
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2025
País:España
Institución:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repositorio:Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:oai:recercat.cat:10230/70326
Acceso en línea:http://hdl.handle.net/10230/70326
http://dx.doi.org/10.1038/s41467-025-57600-4
Access Level:acceso abierto
Palabra clave:Gene expression
Gene expression analysis
Transcriptomics
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spelling A single-cell resolved genotype-phenotype map using genome-wide genetic and environmental perturbationsNadal Ribelles, Mariona, 1984-Solé, CarmeDíez Villanueva, PabloStephan-Otto Attolini, CamilleMatas, YaimaSteinmetz, Lars M.Nadal Clanchet, Eulàlia dePosas Garriga, FrancescGene expressionGene expression analysisTranscriptomicsHeterogeneity is inherent to living organisms and it determines cell fate and phenotypic variability. Despite its ubiquity, the underlying molecular mechanisms and the genetic basis linking genotype to-phenotype heterogeneity remain a central challenge. Here we construct a yeast knockout library with a clone and genotype RNA barcoding structure suitable for genome-scale analyses to generate a high-resolution single-cell yeast transcriptome atlas of 3500 mutants under control and stress conditions. We find that transcriptional heterogeneity reflects the coordinated expression of specific gene programs, generating a continuous of cell states that can be responsive to external insults. Cell state plasticity can be genetically modulated with mutants that act as state attractors and disruption of state homeostasis results in decreased adaptive fitness. Leveraging on intra-genetic variability, we establish that regulators of transcriptional heterogeneity are functionally diverse and influenced by the environment. Our multimodal perturbation-based single-cell Genotype-to-Transcriptome Atlas in yeast provides insights into organism-level responses.This work was founded by MICIU/AEI /10.13039/501100011033 and ERDF/EU to FP and EdN (PID2021-124723NB-C21/C22). Funding from the Ministry of Science, Innovation and Universities through the Centres of Excellence Severo Ochoa Award, and from the CERCA Programme of the Government of Catalonia and the Unidad de Excelencia María de Maeztu, funded by the AEI (CEX2018-000792-M). The Ramon y Cajal Program (Spanish Ministry of Science, RYC2021-033520-I) and La Caixa Junior (LCF/BQ/PR20/11770001) awarded to MNR. FP and EdeN are recipients of an ICREA Acadèmia award (Government of Catalonia).Nature Research202520252025info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfapplication/pdfhttp://hdl.handle.net/10230/70326http://dx.doi.org/10.1038/s41467-025-57600-4reponame:Recercat. Dipósit de la Recerca de Catalunyainstname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)InglésNat Commun. 2025 Mar 18;16(1):2645info:eu-repo/grantAgreement/ES/3PE/PID2021-124723NB-C21info:eu-repo/grantAgreement/ES/3PE/PID2021-124723NB-C22© 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/.http://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:recercat.cat:10230/703262026-05-29T05:05:01Z
dc.title.none.fl_str_mv A single-cell resolved genotype-phenotype map using genome-wide genetic and environmental perturbations
title A single-cell resolved genotype-phenotype map using genome-wide genetic and environmental perturbations
spellingShingle A single-cell resolved genotype-phenotype map using genome-wide genetic and environmental perturbations
Nadal Ribelles, Mariona, 1984-
Gene expression
Gene expression analysis
Transcriptomics
title_short A single-cell resolved genotype-phenotype map using genome-wide genetic and environmental perturbations
title_full A single-cell resolved genotype-phenotype map using genome-wide genetic and environmental perturbations
title_fullStr A single-cell resolved genotype-phenotype map using genome-wide genetic and environmental perturbations
title_full_unstemmed A single-cell resolved genotype-phenotype map using genome-wide genetic and environmental perturbations
title_sort A single-cell resolved genotype-phenotype map using genome-wide genetic and environmental perturbations
dc.creator.none.fl_str_mv Nadal Ribelles, Mariona, 1984-
Solé, Carme
Díez Villanueva, Pablo
Stephan-Otto Attolini, Camille
Matas, Yaima
Steinmetz, Lars M.
Nadal Clanchet, Eulàlia de
Posas Garriga, Francesc
author Nadal Ribelles, Mariona, 1984-
author_facet Nadal Ribelles, Mariona, 1984-
Solé, Carme
Díez Villanueva, Pablo
Stephan-Otto Attolini, Camille
Matas, Yaima
Steinmetz, Lars M.
Nadal Clanchet, Eulàlia de
Posas Garriga, Francesc
author_role author
author2 Solé, Carme
Díez Villanueva, Pablo
Stephan-Otto Attolini, Camille
Matas, Yaima
Steinmetz, Lars M.
Nadal Clanchet, Eulàlia de
Posas Garriga, Francesc
author2_role author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Gene expression
Gene expression analysis
Transcriptomics
topic Gene expression
Gene expression analysis
Transcriptomics
description Heterogeneity is inherent to living organisms and it determines cell fate and phenotypic variability. Despite its ubiquity, the underlying molecular mechanisms and the genetic basis linking genotype to-phenotype heterogeneity remain a central challenge. Here we construct a yeast knockout library with a clone and genotype RNA barcoding structure suitable for genome-scale analyses to generate a high-resolution single-cell yeast transcriptome atlas of 3500 mutants under control and stress conditions. We find that transcriptional heterogeneity reflects the coordinated expression of specific gene programs, generating a continuous of cell states that can be responsive to external insults. Cell state plasticity can be genetically modulated with mutants that act as state attractors and disruption of state homeostasis results in decreased adaptive fitness. Leveraging on intra-genetic variability, we establish that regulators of transcriptional heterogeneity are functionally diverse and influenced by the environment. Our multimodal perturbation-based single-cell Genotype-to-Transcriptome Atlas in yeast provides insights into organism-level responses.
publishDate 2025
dc.date.none.fl_str_mv 2025
2025
2025
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10230/70326
http://dx.doi.org/10.1038/s41467-025-57600-4
url http://hdl.handle.net/10230/70326
http://dx.doi.org/10.1038/s41467-025-57600-4
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Nat Commun. 2025 Mar 18;16(1):2645
info:eu-repo/grantAgreement/ES/3PE/PID2021-124723NB-C21
info:eu-repo/grantAgreement/ES/3PE/PID2021-124723NB-C22
dc.rights.none.fl_str_mv http://creativecommons.org/licenses/by/4.0/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv http://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Nature Research
publisher.none.fl_str_mv Nature Research
dc.source.none.fl_str_mv reponame:Recercat. Dipósit de la Recerca de Catalunya
instname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
instname_str Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
reponame_str Recercat. Dipósit de la Recerca de Catalunya
collection Recercat. Dipósit de la Recerca de Catalunya
repository.name.fl_str_mv
repository.mail.fl_str_mv
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