Effects of Hst3p inhibition in Candida albicans: a genome-wide H3K56 acetylation analysis

Candida spp. represent the third most frequent worldwide cause of infection in Intensive Care Units with a mortality rate of almost 40%. The classes of antifungals currently available include azoles, polyenes, echinocandins, pyrimidine derivatives, and allylamines. However, the therapeutical options...

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Main Authors: Marisa Conte, Daniela Eletto, Martina Pannetta, Anna M. Petrone, Maria C. Monti, Chiara Cassiano, Giorgio Giurato, Francesca Rizzo, Peter Tessarz, Antonello Petrella, Alessandra Tosco, Amalia Porta
Format: Article
Language:English
Published: Frontiers Media S.A. 2022-10-01
Series:Frontiers in Cellular and Infection Microbiology
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Online Access:https://www.frontiersin.org/articles/10.3389/fcimb.2022.1031814/full
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author Marisa Conte
Marisa Conte
Daniela Eletto
Martina Pannetta
Martina Pannetta
Anna M. Petrone
Maria C. Monti
Chiara Cassiano
Chiara Cassiano
Giorgio Giurato
Francesca Rizzo
Peter Tessarz
Peter Tessarz
Antonello Petrella
Alessandra Tosco
Amalia Porta
author_facet Marisa Conte
Marisa Conte
Daniela Eletto
Martina Pannetta
Martina Pannetta
Anna M. Petrone
Maria C. Monti
Chiara Cassiano
Chiara Cassiano
Giorgio Giurato
Francesca Rizzo
Peter Tessarz
Peter Tessarz
Antonello Petrella
Alessandra Tosco
Amalia Porta
author_sort Marisa Conte
collection DOAJ
description Candida spp. represent the third most frequent worldwide cause of infection in Intensive Care Units with a mortality rate of almost 40%. The classes of antifungals currently available include azoles, polyenes, echinocandins, pyrimidine derivatives, and allylamines. However, the therapeutical options for the treatment of candidiasis are drastically reduced by the increasing antifungal resistance. The growing need for a more targeted antifungal therapy is limited by the concern of finding molecules that specifically recognize the microbial cell without damaging the host. Epigenetic writers and erasers have emerged as promising targets in different contexts, including the treatment of fungal infections. In C. albicans, Hst3p, a sirtuin that deacetylates H3K56ac, represents an attractive antifungal target as it is essential for the fungus viability and virulence. Although the relevance of such epigenetic regulator is documented for the development of new antifungal therapies, the molecular mechanism behind Hst3p-mediated epigenetic regulation remains unrevealed. Here, we provide the first genome-wide profiling of H3K56ac in C. albicans resulting in H3K56ac enriched regions associated with Candida sp. pathogenicity. Upon Hst3p inhibition, 447 regions gain H3K56ac. Importantly, these genomic areas contain genes encoding for adhesin proteins, degradative enzymes, and white-opaque switching. Moreover, our RNA-seq analysis revealed 1330 upregulated and 1081 downregulated transcripts upon Hst3p inhibition, and among them, we identified 87 genes whose transcriptional increase well correlates with the enrichment of H3K56 acetylation on their promoters, including some well-known regulators of phenotypic switching and virulence. Based on our evidence, Hst3p is an appealing target for the development of new potential antifungal drugs.
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spelling doaj.art-56a9b7e10a714e649fa4260b51963bdf2022-12-22T03:22:09ZengFrontiers Media S.A.Frontiers in Cellular and Infection Microbiology2235-29882022-10-011210.3389/fcimb.2022.10318141031814Effects of Hst3p inhibition in Candida albicans: a genome-wide H3K56 acetylation analysisMarisa Conte0Marisa Conte1Daniela Eletto2Martina Pannetta3Martina Pannetta4Anna M. Petrone5Maria C. Monti6Chiara Cassiano7Chiara Cassiano8Giorgio Giurato9Francesca Rizzo10Peter Tessarz11Peter Tessarz12Antonello Petrella13Alessandra Tosco14Amalia Porta15Department of Pharmacy, University of Salerno, Fisciano, Salerno, ItalyPh.D. Program in Drug Discovery and Development, University of Salerno, Fisciano, Salerno, ItalyDepartment of Pharmacy, University of Salerno, Fisciano, Salerno, ItalyDepartment of Pharmacy, University of Salerno, Fisciano, Salerno, ItalyPh.D. Program in Drug Discovery and Development, University of Salerno, Fisciano, Salerno, ItalyPh.D. Program in Drug Discovery and Development, University of Salerno, Fisciano, Salerno, ItalyDepartment of Pharmacy, University of Salerno, Fisciano, Salerno, ItalyDepartment of Pharmacy, University of Salerno, Fisciano, Salerno, ItalyDepartment of Pharmacy, University of Naples ‘Federico II’, Naples, ItalyLaboratory of Molecular Medicine and Genomics, Department of Medicine, Surgery and Dentistry “Scuola Medica Salernitana”, University of Salerno, Baronissi, Salerno, ItalyLaboratory of Molecular Medicine and Genomics, Department of Medicine, Surgery and Dentistry “Scuola Medica Salernitana”, University of Salerno, Baronissi, Salerno, ItalyMax Planck Research Group “Chromatin and Ageing”, Max Planck Institute for Biology of Ageing, Cologne, GermanyCologne Excellence Cluster on Stress Responses in Ageing-Associated Diseases (CECAD), University of Cologne, Cologne, GermanyDepartment of Pharmacy, University of Salerno, Fisciano, Salerno, ItalyDepartment of Pharmacy, University of Salerno, Fisciano, Salerno, ItalyDepartment of Pharmacy, University of Salerno, Fisciano, Salerno, ItalyCandida spp. represent the third most frequent worldwide cause of infection in Intensive Care Units with a mortality rate of almost 40%. The classes of antifungals currently available include azoles, polyenes, echinocandins, pyrimidine derivatives, and allylamines. However, the therapeutical options for the treatment of candidiasis are drastically reduced by the increasing antifungal resistance. The growing need for a more targeted antifungal therapy is limited by the concern of finding molecules that specifically recognize the microbial cell without damaging the host. Epigenetic writers and erasers have emerged as promising targets in different contexts, including the treatment of fungal infections. In C. albicans, Hst3p, a sirtuin that deacetylates H3K56ac, represents an attractive antifungal target as it is essential for the fungus viability and virulence. Although the relevance of such epigenetic regulator is documented for the development of new antifungal therapies, the molecular mechanism behind Hst3p-mediated epigenetic regulation remains unrevealed. Here, we provide the first genome-wide profiling of H3K56ac in C. albicans resulting in H3K56ac enriched regions associated with Candida sp. pathogenicity. Upon Hst3p inhibition, 447 regions gain H3K56ac. Importantly, these genomic areas contain genes encoding for adhesin proteins, degradative enzymes, and white-opaque switching. Moreover, our RNA-seq analysis revealed 1330 upregulated and 1081 downregulated transcripts upon Hst3p inhibition, and among them, we identified 87 genes whose transcriptional increase well correlates with the enrichment of H3K56 acetylation on their promoters, including some well-known regulators of phenotypic switching and virulence. Based on our evidence, Hst3p is an appealing target for the development of new potential antifungal drugs.https://www.frontiersin.org/articles/10.3389/fcimb.2022.1031814/fullCandidasirtuinHst3p deacetylaseH3K56 acetylationChIP-seqantifungals
spellingShingle Marisa Conte
Marisa Conte
Daniela Eletto
Martina Pannetta
Martina Pannetta
Anna M. Petrone
Maria C. Monti
Chiara Cassiano
Chiara Cassiano
Giorgio Giurato
Francesca Rizzo
Peter Tessarz
Peter Tessarz
Antonello Petrella
Alessandra Tosco
Amalia Porta
Effects of Hst3p inhibition in Candida albicans: a genome-wide H3K56 acetylation analysis
Frontiers in Cellular and Infection Microbiology
Candida
sirtuin
Hst3p deacetylase
H3K56 acetylation
ChIP-seq
antifungals
title Effects of Hst3p inhibition in Candida albicans: a genome-wide H3K56 acetylation analysis
title_full Effects of Hst3p inhibition in Candida albicans: a genome-wide H3K56 acetylation analysis
title_fullStr Effects of Hst3p inhibition in Candida albicans: a genome-wide H3K56 acetylation analysis
title_full_unstemmed Effects of Hst3p inhibition in Candida albicans: a genome-wide H3K56 acetylation analysis
title_short Effects of Hst3p inhibition in Candida albicans: a genome-wide H3K56 acetylation analysis
title_sort effects of hst3p inhibition in candida albicans a genome wide h3k56 acetylation analysis
topic Candida
sirtuin
Hst3p deacetylase
H3K56 acetylation
ChIP-seq
antifungals
url https://www.frontiersin.org/articles/10.3389/fcimb.2022.1031814/full
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