scholarly journals Role of Ndt80p in Sterol Metabolism Regulation and Azole Resistance in Candida albicans

2009 ◽  
Vol 8 (8) ◽  
pp. 1174-1183 ◽  
Author(s):  
Adnane Sellam ◽  
Faïza Tebbji ◽  
André Nantel
Keyword(s):  
Candida Albicans ◽  
Stress Responses ◽  
Efflux Pump ◽  
Transcriptional Profiling ◽  
Ergosterol Biosynthesis ◽  
Gene Promoters ◽  
Sterol Metabolism ◽  
Metabolism Regulation ◽  
Genome Wide

ABSTRACT The Ndt80p transcription factor modulates azole tolerance in Candida albicans by controlling the expression of the gene for the drug efflux pump Cdr1p. To date, the contribution of this transcriptional modulator to drug tolerance is not yet well understood. Here, we investigate the role of Ndt80p in mediating fluconazole tolerance by determining its genome-wide occupancy using chromatin immunoprecipitation coupled to high-density tiling arrays. Ndt80p was found to bind a large number of gene promoters with diverse biological functions. Gene ontology analysis of these Ndt80p targets revealed a significant enrichment in gene products related to the cell wall, carbohydrate metabolism, stress responses, hyphal development, multidrug transport, and the cell cycle. Ndt80p was found on the promoters of ergosterol biosynthesis genes, including on the azole target Erg11p. Additionally, expression profiling was used to identify fluconazole-responsive genes that require Ndt80p for their proper expression. We found that Ndt80p is crucial for the expression of numerous fluconazole-responsive genes, especially genes involved in ergosterol metabolism. Therefore, by combining genome-wide location and transcriptional profiling, we have characterized the Ndt80p fluconazole-dependent regulon and demonstrated the key role of this global transcriptional regulator in modulating sterol metabolism and drug resistance in C. albicans.

scholarly journals In VitroEffect of Malachite Green on Candida albicans Involves Multiple Pathways and Transcriptional RegulatorsUPC2andSTP2

2011 ◽  
Vol 56 (1) ◽  
pp. 495-506 ◽  
Author(s):  
Sanjiveeni Dhamgaye ◽  
Frederic Devaux ◽  
Raman Manoharlal ◽  
Patrick Vandeputte ◽  
Abdul Haseeb Shah ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Amino Acid ◽  
Malachite Green ◽  
Efflux Pump ◽  
Iron Acquisition ◽  
Transcriptional Profiling ◽  
Ergosterol Biosynthesis ◽  
Intracellular Iron ◽  
Amino Acid Permease ◽  
Content Type

ABSTRACTIn this study, we show that a chemical dye, malachite green (MG), which is commonly used in the fish industry as an antifungal, antiparasitic, and antibacterial agent, could effectively killCandida albicansand non-C. albicansspecies. We have demonstrated thatCandidacells are susceptible to MG at a very low concentration (MIC that reduces growth by 50% [MIC50], 100 ng ml−1) and that the effect of MG is independent of known antifungal targets, such as ergosterol metabolism and major drug efflux pump proteins. Transcriptional profiling in response to MG treatment ofC. albicanscells revealed that of a total of 207 responsive genes, 167 genes involved in oxidative stress, virulence, carbohydrate metabolism, heat shock, amino acid metabolism, etc., were upregulated, while 37 genes involved in iron acquisition, filamentous growth, mitochondrial respiration, etc., were downregulated. We confirmed experimentally thatCandidacells exposed to MG resort to a fermentative mode of metabolism, perhaps due to defective respiration. In addition, we showed that MG triggers depletion of intracellular iron pools and enhances reactive oxygen species (ROS) levels. These effects could be reversed by the addition of iron or antioxidants, respectively. We provided evidence that the antifungal effect of MG is exerted through the transcription regulatorsUPC2(regulating ergosterol biosynthesis and azole resistance) andSTP2(regulating amino acid permease genes). Taken together, our transcriptome, genetic, and biochemical results allowed us to decipher the multiple mechanisms by which MG exerts its anti-Candidaeffects, leading to a metabolic shift toward fermentation, increased generation of ROS, labile iron deprivation, and cell necrosis.

scholarly journals Comprehensive Genomic Discovery of Non-Coding Transcriptional Enhancers in the African Malaria Vector Anopheles coluzzii

2022 ◽  
Vol 12 ◽  
Author(s):  
Inge Holm ◽  
Luisa Nardini ◽  
Adrien Pain ◽  
Emmanuel Bischoff ◽  
Cameron E. Anderson ◽  
...  
Keyword(s):  
Malaria Vector ◽  
Regulatory Elements ◽  
Specific Cell ◽  
Insect Vector ◽  
Anopheles Coluzzii ◽  
Gene Promoters ◽  
Transcriptional Enhancers ◽  
Genome Wide ◽  
A Genome

Almost all regulation of gene expression in eukaryotic genomes is mediated by the action of distant non-coding transcriptional enhancers upon proximal gene promoters. Enhancer locations cannot be accurately predicted bioinformatically because of the absence of a defined sequence code, and thus functional assays are required for their direct detection. Here we used a massively parallel reporter assay, Self-Transcribing Active Regulatory Region sequencing (STARR-seq), to generate the first comprehensive genome-wide map of enhancers in Anopheles coluzzii, a major African malaria vector in the Gambiae species complex. The screen was carried out by transfecting reporter libraries created from the genomic DNA of 60 wild A. coluzzii from Burkina Faso into A. coluzzii 4a3A cells, in order to functionally query enhancer activity of the natural population within the homologous cellular context. We report a catalog of 3,288 active genomic enhancers that were significant across three biological replicates, 74% of them located in intergenic and intronic regions. The STARR-seq enhancer screen is chromatin-free and thus detects inherent activity of a comprehensive catalog of enhancers that may be restricted in vivo to specific cell types or developmental stages. Testing of a validation panel of enhancer candidates using manual luciferase assays confirmed enhancer function in 26 of 28 (93%) of the candidates over a wide dynamic range of activity from two to at least 16-fold activity above baseline. The enhancers occupy only 0.7% of the genome, and display distinct composition features. The enhancer compartment is significantly enriched for 15 transcription factor binding site signatures, and displays divergence for specific dinucleotide repeats, as compared to matched non-enhancer genomic controls. The genome-wide catalog of A. coluzzii enhancers is publicly available in a simple searchable graphic format. This enhancer catalogue will be valuable in linking genetic and phenotypic variation, in identifying regulatory elements that could be employed in vector manipulation, and in better targeting of chromosome editing to minimize extraneous regulation influences on the introduced sequences.Importance: Understanding the role of the non-coding regulatory genome in complex disease phenotypes is essential, but even in well-characterized model organisms, identification of regulatory regions within the vast non-coding genome remains a challenge. We used a large-scale assay to generate a genome wide map of transcriptional enhancers. Such a catalogue for the important malaria vector, Anopheles coluzzii, will be an important research tool as the role of non-coding regulatory variation in differential susceptibility to malaria infection is explored and as a public resource for research on this important insect vector of disease.

scholarly journals Candida albicans Transcriptional Profiling Within Biliary Fluid From a Patient With Cholangitis, Before and After Antifungal Treatment and Surgical Drainage

2016 ◽  
Vol 3 (3) ◽  
Author(s):  
Cornelius J. Clancy ◽  
Camille Meslin ◽  
Hassan Badrane ◽  
Shaoji Cheng ◽  
Liliana C. Losada ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Transcriptional Profiling ◽  
Hyphal Growth ◽  
Global Gene Expression ◽  
Human Infection ◽  
Ergosterol Biosynthesis ◽  
Infection Site ◽  
Oxidation Reduction ◽  
Cell Wall Organization ◽  
Before And After

Abstract We used ribonucleic acid sequencing to profile Candida albicans transcription within biliary fluid from a patient with cholangitis; samples were collected before and after treatment with fluconazole and drainage. Candida albicans transcriptomes at the infection site distinguished treated from untreated cholangitis. After treatment, 1131 C. albicans genes were differentially expressed in biliary fluid. Up-regulated genes were enriched in hyphal growth, cell wall organization, adhesion, oxidation reduction, biofilm, and fatty acid and ergosterol biosynthesis. This is the first study to define Candida global gene expression during deep-seated human infection. Successful treatment of cholangitis induced C. albicans genes involved in fluconazole responses and pathogenesis.

scholarly journals Role of Calprotectin in Withholding Zinc and Copper from Candida albicans

2017 ◽  
Vol 86 (2) ◽  
Author(s):  
Angelique N. Besold ◽  
Benjamin A. Gilston ◽  
Jana N. Radin ◽  
Christian Ramsoomair ◽  
Edward M. Culbertson ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Stress Responses ◽  
Metal Binding ◽  
Content Type ◽  
Nutritional Immunity ◽  
Numerous Cell ◽  
Transcriptional Changes ◽  
Opportunistic Fungal Pathogen ◽  
First Time

ABSTRACT The opportunistic fungal pathogen Candida albicans acquires essential metals from the host, yet the host can sequester these micronutrients through a process known as nutritional immunity. How the host withholds metals from C. albicans has been poorly understood; here we examine the role of calprotectin (CP), a transition metal binding protein. When CP depletes bioavailable Zn from the extracellular environment, C. albicans strongly upregulates ZRT1 and PRA1 for Zn import and maintains constant intracellular Zn through numerous cell divisions. We show for the first time that CP can also sequester Cu by binding Cu(II) with subpicomolar affinity. CP blocks fungal acquisition of Cu from serum and induces a Cu starvation stress response involving SOD1 and SOD3 superoxide dismutases. These transcriptional changes are mirrored when C. albicans invades kidneys in a mouse model of disseminated candidiasis, although the responses to Cu and Zn limitations are temporally distinct. The Cu response progresses throughout 72 h, while the Zn response is short-lived. Notably, these stress responses were attenuated in CP null mice, but only at initial stages of infection. Thus, Zn and Cu pools are dynamic at the host-pathogen interface and CP acts early in infection to restrict metal nutrients from C. albicans.

scholarly journals Role of the RAM Network in Cell Polarity and Hyphal Morphogenesis inCandida albicans

2008 ◽  
Vol 19 (12) ◽  
pp. 5456-5477 ◽  
Author(s):  
Yunkyoung Song ◽  
Seon Ah Cheon ◽  
Kyung Eun Lee ◽  
So-Yeon Lee ◽  
Byung-Kyu Lee ◽  
...  
Keyword(s):  
Cell Polarity ◽  
Direct Interaction ◽  
Hyphal Growth ◽  
Ergosterol Biosynthesis ◽  
Hyphal Morphogenesis ◽  
Genome Wide ◽  
Ram Network ◽  
Functional Analyses

RAM (regulation of Ace2p transcription factor and polarized morphogenesis) is a conserved signaling network that regulates polarized morphogenesis in yeast, worms, flies, and humans. To investigate the role of the RAM network in cell polarity and hyphal morphogenesis of Candida albicans, each of the C. albicans RAM genes (CaCBK1, CaMOB2, CaKIC1, CaPAG1, CaHYM1, and CaSOG2) was deleted. All C. albicans RAM mutants exhibited hypersensitivity to cell-wall- or membrane-perturbing agents, exhibiting cell-separation defects, a multinucleate phenotype and loss of cell polarity. Yeast two-hybrid and in vivo functional analyses of CaCbk1p and its activator, CaMob2p, the key factors in the RAM network, demonstrated that the direct interaction between the SMA domain of CaCbk1p and the Mob1/phocein domain of CaMob2p was necessary for hyphal growth of C. albicans. Genome-wide transcription profiling of a Camob2 mutant suggested that the RAM network played a role in serum- and antifungal azoles–induced activation of ergosterol biosynthesis genes, especially those involved in the late steps of ergosterol biosynthesis, and might be associated, at least indirectly, with the Tup1p-Nrg1p pathway. Collectively, these results demonstrate that the RAM network is critically required for hyphal growth as well as normal vegetative growth in C. albicans.

scholarly journals A Role for Gcn5-Mediated Global Histone Acetylation in Transcriptional Regulation

2006 ◽  
Vol 26 (5) ◽  
pp. 1610-1616 ◽  
Author(s):  
Rachel Maria Imoberdorf ◽  
Irini Topalidou ◽  
Michel Strubin
Keyword(s):  
Histone Acetylation ◽  
Core Promoter ◽  
Histone Acetyltransferases ◽  
Gene Promoters ◽  
Core Promoters ◽  
The Core ◽  
Strength Of Interaction ◽  
Genome Wide ◽  
The Common

ABSTRACT Transcriptional activators often require histone acetyltransferases (HATs) for full activity. The common explanation is that activators directly recruit HATs to gene promoters to locally hyperacetylate histones and thereby facilitate transcription complex formation. However, in addition to being targeted to specific loci, HATs such as Gcn5 also modify histones genome-wide. Here we provide evidence for a role of this global HAT activity in regulated transcription. We show that activation by direct recruitment of the transcriptional machinery neither recruits Gcn5 nor induces changes in histone acetylation yet can strongly depend on Gcn5 at promoters showing a high basal state of Gcn5-mediated histone acetylation. We also show that Gcn5 dependency varies among core promoters and is influenced by the strength of interaction used to recruit the machinery and by the affinity of the latter for the core promoter. These data support a role for global Gcn5 HAT activity in modulating transcription independently of its known coactivator function.

scholarly journals Transcriptional activity of TRF2 is telomere length dependent

2016 ◽  
Author(s):  
Ananda Kishore Mukherjee ◽  
Shalu Sharma ◽  
Parashar Dhapola ◽  
Dhurjhoti Saha ◽  
Tabish Hussain ◽  
...  
Keyword(s):  
Telomere Length ◽  
Genome Stability ◽  
Telomere Maintenance ◽  
Regulatory Control ◽  
Gene Promoters ◽  
Multiple Gene ◽  
Telomere Repeat ◽  
Genome Wide ◽  
Binding Factor

AbstractTRF2 is a telomere repeat binding factor crucial for telomere maintenance and genome stability. An emerging non-conventional role of TRF2 is as a transcriptional regulator through extra-telomeric bindings. Herein we report that increase in telomere length leads to sequestration of TRF2 at the telomeres leading to reduced extra-telomeric TRF2 occupancy genome wide. Decrease in TRF2 occupancy was found on multiple gene promoters in cells with elongated telomeres, including the cell cycle regulator kinase-p21. We found that TRF2 is a transcriptional repressor of p21, and, interestingly, TRF2-mediated regulatory control of p21 is telomere length dependent.

scholarly journals Adaptive growth homeostasis in response to drought in Iberian Arabidopsis accessions

2021 ◽  
Author(s):  
Ángel Ferrero-Serrano ◽  
Sarah M Assmann
Keyword(s):  
Leaf Area ◽  
Stress Responses ◽  
Association Studies ◽  
Transport Processes ◽  
Functional Enrichment ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Genome Wide ◽  
Intrinsic Water Use Efficiency

Plants respond to environmental fluctuations through plastic phenotypic shifts. Whether a plastic response upon environmental variability is adaptive or not has been subject to debate. Using a set of Iberian Arabidopsis accessions, we quantified an interplay between passive plastic reductions in leaf areas that we found typical of accessions from productive environments and homeostatic leaf areas responses to drought typified by accessions originating from unproductive environments. Results from Genome-Wide Association Studies (GWAS) and Transcriptome Wide Association Studies (TWAS) highlight the role of auxin-related processes and, in particular, the possible role of the SMALL AUXIN UP RNA 26 (SAUR26) gene in the regulation of the observed plastic responses. Homeostatic responses in leaf area potential following drought were typical of accessions with lower leaf area potential under well-watered conditions. Transcripts that were negatively associated with leaf area potential and positively associated with homeostatic and positive leaf area plasticity following drought showed functional enrichment in ion transport processes. We hypothesized that the contrasting plastic and homeostatic responses in leaf area potential were associated with differential intrinsic water use efficiency (WUEi). We confirmed this relationship in a metanalysis conducted using previously published δ13C measurements. Our results highlight the adaptive role of homeostatic leaf area response to water depletion arising from increased WUEi. The concerted utilization of Genome-Wide Association Studies (GWAS), Transcriptome Wide Association Studies (TWAS), and expression Genome-Wide Association Studies (eGWAS) allows integration of phenotype, genotype, and transcript abundance to identify both "plasticity genes" and "homeostasis genes" associated with drought stress responses.

Genome-wide transcriptional profiling of the response of Staphylococcus aureus to cell-wall-active antibiotics reveals a cell-wall-stress stimulon

Microbiology ◽  
2003 ◽  
Vol 149 (10) ◽  
pp. 2719-2732 ◽  
Author(s):  
S. Utaida ◽  
P. M. Dunman ◽  
D. Macapagal ◽  
E. Murphy ◽  
S. J. Projan ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Cell Wall ◽  
Stress Responses ◽  
Transcriptional Profiling ◽  
Wall Stress ◽  
Antibacterial Activities ◽  
Transcriptional Signature ◽  
Genome Wide ◽  
Custom Made ◽  
A Cell

The molecular events following inhibition of bacterial peptidoglycan synthesis have not been studied extensively. Previous proteomic studies have revealed that certain proteins are produced in increased amounts upon challenge of Staphylococcus aureus with cell-wall-active antibiotics. In an effort to further those studies, the genes upregulated in their expression in response to cell-wall-active antibiotics have been identified by genome-wide transcriptional profiling using custom-made Affymetrix S. aureus GeneChipsTM. A large number of genes, including ones encoding proteins involved in cell-wall metabolism (including pbpB, murZ, fmt and vraS) and stress responses (including msrA, htrA, psrA and hslO), were upregulated by oxacillin, d-cycloserine or bacitracin. This response may represent the transcriptional signature of a cell-wall stimulon induced in response to cell-wall-active agents. The findings imply that treatment with cell-wall-active antibiotics results in damage to proteins including oxidative damage. Additional genes in a variety of functional categories were upregulated uniquely by each of the three cell-wall-active antibiotics studied. These changes in gene expression can be viewed as an attempt by the organism to defend itself against the antibacterial activities of the agents.

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