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Genetic interaction networks mediate individual statin drug response in Saccharomyces cerevisiae

Eukaryotic genetic interaction networks (GINs) are extensively described in the Saccharomyces cerevisiae S288C model using deletion libraries, yet being limited to this one genetic background, not informative to individual drug response. Here we created deletion libraries in three additional genetic...

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Autores principales: Busby, Bede P., Niktab, Eliatan, Roberts, Christina A., Sheridan, Jeffrey P., Coorey, Namal V., Senanayake, Dinindu S., Connor, Lisa M., Munkacsi, Andrew B., Atkinson, Paul H.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6776536/
https://www.ncbi.nlm.nih.gov/pubmed/31602312
http://dx.doi.org/10.1038/s41540-019-0112-5
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author Busby, Bede P.
Niktab, Eliatan
Roberts, Christina A.
Sheridan, Jeffrey P.
Coorey, Namal V.
Senanayake, Dinindu S.
Connor, Lisa M.
Munkacsi, Andrew B.
Atkinson, Paul H.
author_facet Busby, Bede P.
Niktab, Eliatan
Roberts, Christina A.
Sheridan, Jeffrey P.
Coorey, Namal V.
Senanayake, Dinindu S.
Connor, Lisa M.
Munkacsi, Andrew B.
Atkinson, Paul H.
author_sort Busby, Bede P.
collection PubMed
description Eukaryotic genetic interaction networks (GINs) are extensively described in the Saccharomyces cerevisiae S288C model using deletion libraries, yet being limited to this one genetic background, not informative to individual drug response. Here we created deletion libraries in three additional genetic backgrounds. Statin response was probed with five queries against four genetic backgrounds. The 20 resultant GINs representing drug–gene and gene–gene interactions were not conserved by functional enrichment, hierarchical clustering, and topology-based community partitioning. An unfolded protein response (UPR) community exhibited genetic background variation including different betweenness genes that were network bottlenecks, and we experimentally validated this UPR community via measurements of the UPR that were differentially activated and regulated in statin-resistant strains relative to the statin-sensitive S288C background. These network analyses by topology and function provide insight into the complexity of drug response influenced by genetic background.
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spelling pubmed-67765362019-10-10 Genetic interaction networks mediate individual statin drug response in Saccharomyces cerevisiae Busby, Bede P. Niktab, Eliatan Roberts, Christina A. Sheridan, Jeffrey P. Coorey, Namal V. Senanayake, Dinindu S. Connor, Lisa M. Munkacsi, Andrew B. Atkinson, Paul H. NPJ Syst Biol Appl Article Eukaryotic genetic interaction networks (GINs) are extensively described in the Saccharomyces cerevisiae S288C model using deletion libraries, yet being limited to this one genetic background, not informative to individual drug response. Here we created deletion libraries in three additional genetic backgrounds. Statin response was probed with five queries against four genetic backgrounds. The 20 resultant GINs representing drug–gene and gene–gene interactions were not conserved by functional enrichment, hierarchical clustering, and topology-based community partitioning. An unfolded protein response (UPR) community exhibited genetic background variation including different betweenness genes that were network bottlenecks, and we experimentally validated this UPR community via measurements of the UPR that were differentially activated and regulated in statin-resistant strains relative to the statin-sensitive S288C background. These network analyses by topology and function provide insight into the complexity of drug response influenced by genetic background. Nature Publishing Group UK 2019-10-03 /pmc/articles/PMC6776536/ /pubmed/31602312 http://dx.doi.org/10.1038/s41540-019-0112-5 Text en © The Author(s) 2019 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 license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license 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 license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Busby, Bede P.
Niktab, Eliatan
Roberts, Christina A.
Sheridan, Jeffrey P.
Coorey, Namal V.
Senanayake, Dinindu S.
Connor, Lisa M.
Munkacsi, Andrew B.
Atkinson, Paul H.
Genetic interaction networks mediate individual statin drug response in Saccharomyces cerevisiae
title Genetic interaction networks mediate individual statin drug response in Saccharomyces cerevisiae
title_full Genetic interaction networks mediate individual statin drug response in Saccharomyces cerevisiae
title_fullStr Genetic interaction networks mediate individual statin drug response in Saccharomyces cerevisiae
title_full_unstemmed Genetic interaction networks mediate individual statin drug response in Saccharomyces cerevisiae
title_short Genetic interaction networks mediate individual statin drug response in Saccharomyces cerevisiae
title_sort genetic interaction networks mediate individual statin drug response in saccharomyces cerevisiae
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6776536/
https://www.ncbi.nlm.nih.gov/pubmed/31602312
http://dx.doi.org/10.1038/s41540-019-0112-5
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