SWI/SNF and the histone chaperone Rtt106 drive expression of the Pleiotropic Drug Resistance network genes

Vladislav Nikolov; Dhara Malavia; Takashi Kubota

doi:10.1038/s41467-022-29591-z

SWI/SNF and the histone chaperone Rtt106 drive expression of the Pleiotropic Drug Resistance network genes

Vladislav Nikolov, Dhara Malavia, Takashi Kubota^* (Corresponding Author)

^*Corresponding author for this work

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Abstract

The Pleiotropic Drug Resistance (PDR) network is central to the drug response in fungi, and its overactivation is associated with drug resistance. However, gene regulation of the PDR network is not well understood. Here, we show that the histone chaperone Rtt106 and the chromatin remodeller SWI/SNF control expression of the PDR network genes and confer drug resistance. In Saccharomyces cerevisiae, Rtt106 specifically localises to PDR network gene promoters dependent on transcription factor Pdr3, but not Pdr1, and is essential for Pdr3-mediated basal expression of the PDR network genes, while SWI/SNF is essential for both basal and drug-induced expression. Also in the pathogenic fungus Candida glabrata, Rtt106 and SWI/SNF regulate drug-induced PDR gene expression. Consistently, loss of Rtt106 or SWI/SNF sensitises drug-resistant S. cerevisiae mutants and C. glabrata to antifungal drugs. Since they cooperatively drive PDR network gene expression, Rtt106 and SWI/SNF represent potential therapeutic targets to combat antifungal resistance.

Original language	English
Article number	1968
Number of pages	16
Journal	Nature Communications
Volume	13
Early online date	12 Apr 2022
DOIs	https://doi.org/10.1038/s41467-022-29591-z
Publication status	Published - 12 Apr 2022

Bibliographical note

Acknowledgements
We thank Karl Kuchler, Carol Munro, Donna MacCallum, Delma Childers and Ian Stansfield for plasmids and strains; Ben Rutter, Madeleine Murray and Tom Jayasekara for help with material constructions and homology search; Vamsi Gali, Anne Donaldson, Yuki Katou and Katsuhiko Shirahige for preliminary ChIP-seq data; Shin-ichiro Hiraga for MaxQuant analysis; Stefan Hoppler for access for equipment; Sophie Shaw and Antonio Ribeiro for bioinformatic analysis of the RNA-seq data and also data uploading to ArrayExpress and Anne Donaldson and Alexander Lorenz for careful reading of the manuscript. We are grateful to the core facilities at University of Aberdeen: the CGEBM facility for help with ChIP-seq and RNA-seq (Ewan Campbell and Zeynab Heidari), the Proteomics facility for mass spectrometry (David Stead) and the qPCR facility. Work was supported by Medical Research Council (MRC) Career Development Fellowship L019698/1 to T.K., and Wellcome Trust Strategic Award for Medical Mycology and Fungal Immunology 097377/Z/11/Z to T.K. and D.M.

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abstract = "The Pleiotropic Drug Resistance (PDR) network is central to the drug response in fungi, and its overactivation is associated with drug resistance. However, gene regulation of the PDR network is not well understood. Here, we show that the histone chaperone Rtt106 and the chromatin remodeller SWI/SNF control expression of the PDR network genes and confer drug resistance. In Saccharomyces cerevisiae, Rtt106 specifically localises to PDR network gene promoters dependent on transcription factor Pdr3, but not Pdr1, and is essential for Pdr3-mediated basal expression of the PDR network genes, while SWI/SNF is essential for both basal and drug-induced expression. Also in the pathogenic fungus Candida glabrata, Rtt106 and SWI/SNF regulate drug-induced PDR gene expression. Consistently, loss of Rtt106 or SWI/SNF sensitises drug-resistant S. cerevisiae mutants and C. glabrata to antifungal drugs. Since they cooperatively drive PDR network gene expression, Rtt106 and SWI/SNF represent potential therapeutic targets to combat antifungal resistance.",

author = "Vladislav Nikolov and Dhara Malavia and Takashi Kubota",

note = "Acknowledgements We thank Karl Kuchler, Carol Munro, Donna MacCallum, Delma Childers and Ian Stansfield for plasmids and strains; Ben Rutter, Madeleine Murray and Tom Jayasekara for help with material constructions and homology search; Vamsi Gali, Anne Donaldson, Yuki Katou and Katsuhiko Shirahige for preliminary ChIP-seq data; Shin-ichiro Hiraga for MaxQuant analysis; Stefan Hoppler for access for equipment; Sophie Shaw and Antonio Ribeiro for bioinformatic analysis of the RNA-seq data and also data uploading to ArrayExpress and Anne Donaldson and Alexander Lorenz for careful reading of the manuscript. We are grateful to the core facilities at University of Aberdeen: the CGEBM facility for help with ChIP-seq and RNA-seq (Ewan Campbell and Zeynab Heidari), the Proteomics facility for mass spectrometry (David Stead) and the qPCR facility. Work was supported by Medical Research Council (MRC) Career Development Fellowship L019698/1 to T.K., and Wellcome Trust Strategic Award for Medical Mycology and Fungal Immunology 097377/Z/11/Z to T.K. and D.M.",

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N1 - Acknowledgements We thank Karl Kuchler, Carol Munro, Donna MacCallum, Delma Childers and Ian Stansfield for plasmids and strains; Ben Rutter, Madeleine Murray and Tom Jayasekara for help with material constructions and homology search; Vamsi Gali, Anne Donaldson, Yuki Katou and Katsuhiko Shirahige for preliminary ChIP-seq data; Shin-ichiro Hiraga for MaxQuant analysis; Stefan Hoppler for access for equipment; Sophie Shaw and Antonio Ribeiro for bioinformatic analysis of the RNA-seq data and also data uploading to ArrayExpress and Anne Donaldson and Alexander Lorenz for careful reading of the manuscript. We are grateful to the core facilities at University of Aberdeen: the CGEBM facility for help with ChIP-seq and RNA-seq (Ewan Campbell and Zeynab Heidari), the Proteomics facility for mass spectrometry (David Stead) and the qPCR facility. Work was supported by Medical Research Council (MRC) Career Development Fellowship L019698/1 to T.K., and Wellcome Trust Strategic Award for Medical Mycology and Fungal Immunology 097377/Z/11/Z to T.K. and D.M.

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N2 - The Pleiotropic Drug Resistance (PDR) network is central to the drug response in fungi, and its overactivation is associated with drug resistance. However, gene regulation of the PDR network is not well understood. Here, we show that the histone chaperone Rtt106 and the chromatin remodeller SWI/SNF control expression of the PDR network genes and confer drug resistance. In Saccharomyces cerevisiae, Rtt106 specifically localises to PDR network gene promoters dependent on transcription factor Pdr3, but not Pdr1, and is essential for Pdr3-mediated basal expression of the PDR network genes, while SWI/SNF is essential for both basal and drug-induced expression. Also in the pathogenic fungus Candida glabrata, Rtt106 and SWI/SNF regulate drug-induced PDR gene expression. Consistently, loss of Rtt106 or SWI/SNF sensitises drug-resistant S. cerevisiae mutants and C. glabrata to antifungal drugs. Since they cooperatively drive PDR network gene expression, Rtt106 and SWI/SNF represent potential therapeutic targets to combat antifungal resistance.

AB - The Pleiotropic Drug Resistance (PDR) network is central to the drug response in fungi, and its overactivation is associated with drug resistance. However, gene regulation of the PDR network is not well understood. Here, we show that the histone chaperone Rtt106 and the chromatin remodeller SWI/SNF control expression of the PDR network genes and confer drug resistance. In Saccharomyces cerevisiae, Rtt106 specifically localises to PDR network gene promoters dependent on transcription factor Pdr3, but not Pdr1, and is essential for Pdr3-mediated basal expression of the PDR network genes, while SWI/SNF is essential for both basal and drug-induced expression. Also in the pathogenic fungus Candida glabrata, Rtt106 and SWI/SNF regulate drug-induced PDR gene expression. Consistently, loss of Rtt106 or SWI/SNF sensitises drug-resistant S. cerevisiae mutants and C. glabrata to antifungal drugs. Since they cooperatively drive PDR network gene expression, Rtt106 and SWI/SNF represent potential therapeutic targets to combat antifungal resistance.

U2 - 10.1038/s41467-022-29591-z

DO - 10.1038/s41467-022-29591-z

M3 - Article

SN - 2041-1723

VL - 13

JO - Nature Communications

JF - Nature Communications

M1 - 1968

ER -

SWI/SNF and the histone chaperone Rtt106 drive expression of the Pleiotropic Drug Resistance network genes

Abstract

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