In medical mycology, epigenetic mechanisms are emerging as key regulators of multiple aspects of fungal biology ranging from development, phenotypic and morphological plasticity to antifungal drug resistance. Emerging resistance to the limited therapeutic options for the treatment of invasive fungal infections is a growing concern. Human fungal pathogens develop drug resistance via multiple mechanisms, with recent studies highlighting the role of epigenetic changes involving the acetylation and methylation of histones, remodeling of chromatin and heterochromatin-based gene silencing, in the acquisition of antifungal resistance. A comprehensive understanding of how pathogens acquire drug resistance will aid the development of new antifungal therapies as well as increase the efficacy of current antifungals by blocking common drug-resistance mechanisms. In this article, we describe the epigenetic mechanisms that affect resistance towards widely used systemic antifungal drugs: azoles, echinocandins and polyenes. Additionally, we review the literature on the possible links between DNA mismatch repair, gene silencing and drug-resistance mechanisms.

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Epigenetic Regulation of Antifungal Drug Resistance

Molecular mechanisms governing antifungal drug resistance

Immune evasion is critical for fungal virulence. However, how the human opportunistic pathogen Candida glabrata ( Cg ) accomplishes this is unknown. Here, using micrococcal nuclease-sequencing, RNA-sequencing, macrophage-signalling and genetic analyses, we demonstrate that chromatin remodelling in macrophage-internalized Cg , via CgSnf2 [SWI/SNF chromatin remodelling complex-ATPase subunit], leads to transcriptional upregulation and downregulation of immunosuppressive seven-gene mannosyltransferase-cluster ( CgMT-C ) and immunostimulatory cell surface adhesin-encoding EPA1 gene, respectively. Consistently, EPA1 overexpression and CgMT-C deletion led to increased proinflammatory cytokine IL-1  production and reduced Cg proliferation in macrophages. Further, CgSNF2 deletion evoked increased IL-1  secretion, and the consequent killing of macrophage-internalized Cg , with elevated IL-1  levels reversed partially in Akt-, p38-, NF- B- or NLRP3 inflammasome-inhibited macrophages. Importantly, macrophages respond to multiple Candida pathogens via NF-  B-dependent IL-1  production, underscoring NF-  B signalling’s role in fungal diseases. Altogether, our findings directly link nucleosome positioning-based chromatin remodelling to fungal immunomodulatory molecule expression, which dictates Cg fate in host immune cells.

SWI/SNF complex-mediated chromatin remodelling is vital for cell surface adhesin repression and immune evasion

Immune evasion is critical for fungal virulence. However, how the human opportunistic pathogen Candida glabrata (Cg) accomplishes this is unknown. Here, using micrococcal nuclease-sequencing, RNA-sequencing, macrophage-signalling and genetic analyses, we demonstrate that chromatin reorganization in macrophage-internalized Cg, via CgSnf2 (ATPase subunit of the SWI/SNF chromatin remodelling complex), leads to upregulation and downregulation of immunosuppressive seven mannosyltransferase-cluster (CgMT-C) and immunostimulatory cell surface adhesin EPA1 genes, respectively. Consistently, EPA1 overexpression and CgMT-C deletion led to increased IL-1β (pro-inflammatory cytokine) production and reduced Cg proliferation in macrophages. Further, CgSNF2 deletion evoked increased IL-1β secretion, and the consequent killing of macrophage-internalized Cg, with elevated IL-1β levels being partially reversed in Akt-, p38-, NF-κB- or NLRP3 inflammasome-inhibited macrophages. Importantly, macrophages respond to multiple Candida pathogens via NF-κB-dependent IL-1β production, underscoring NF-κB signalling’s role in fungal diseases. Finally, we present the first genome-wide nucleosome map of macrophage-internalized Cg consisting of ∼12,000 dynamic and 70,000 total nucleosomes. Altogether, our findings directly link the nucleosome positioning-based chromatin remodelling to fungal immunomodulatory molecule expression, which dictates Cg fate in host immune cells.

/pdf/swi-snf-complex-mediated-chromatin-remodelling-in-candida-jjo2hmfj.pdf

SWI/SNF complex-mediated chromatin remodelling in Candida glabrata is vital for immune evasion

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. 

/pdf/swi-snf-and-the-histone-chaperone-rtt106-drive-expression-of-11q7va21.pdf

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

/pdf/swi-snf-and-the-histone-chaperone-rtt106-drive-expression-of-3f5iig78.pdf

Vladislav N Nikolov

Papers

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

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