scholarly journals Dynamic genome plasticity during unisexual reproduction in the human fungal pathogen Cryptococcus deneoformans

PLoS Genetics ◽  
2021 ◽  
Vol 17 (11) ◽  
pp. e1009935
Author(s):  
Ci Fu ◽  
Aaliyah Davy ◽  
Simeon Holmes ◽  
Sheng Sun ◽  
Vikas Yadav ◽  
...  
Keyword(s):  
Fungal Pathogen ◽  
Copy Number ◽  
Molecular Mechanisms ◽  
Chromosome Instability ◽  
Human Fungal Pathogen ◽  
Unisexual Reproduction ◽  
Genes Encoding ◽  
Dynamic Genome ◽  
Selection For ◽  
Regulator Genes

Genome copy number variation occurs during each mitotic and meiotic cycle and it is crucial for organisms to maintain their natural ploidy. Defects in ploidy transitions can lead to chromosome instability, which is a hallmark of cancer. Ploidy in the haploid human fungal pathogen Cryptococcus neoformans is exquisitely orchestrated and ranges from haploid to polyploid during sexual development and under various environmental and host conditions. However, the mechanisms controlling these ploidy transitions are largely unknown. During C. deneoformans (formerly C. neoformans var. neoformans, serotype D) unisexual reproduction, ploidy increases prior to the onset of meiosis, can be independent from cell-cell fusion and nuclear fusion, and likely occurs through an endoreplication pathway. To elucidate the molecular mechanisms underlying this ploidy transition, we identified twenty cell cycle-regulating genes encoding cyclins, cyclin-dependent kinases (CDK), and CDK regulators. We characterized four cyclin genes and two CDK regulator genes that were differentially expressed during unisexual reproduction and contributed to diploidization. To detect ploidy transition events, we generated a ploidy reporter, called NURAT, which can detect copy number increases via double selection for nourseothricin-resistant, uracil-prototrophic cells. Utilizing this ploidy reporter, we showed that ploidy transition from haploid to diploid can be detected during the early phases of unisexual reproduction. Interestingly, selection for the NURAT reporter revealed several instances of segmental aneuploidy of multiple chromosomes, which conferred azole resistance in some isolates. These findings provide further evidence of ploidy plasticity in fungi with significant biological and public health implications.

scholarly journals Dynamic genome plasticity during unisexual reproduction in the human fungal pathogen Cryptococcus deneoformans

2021 ◽  
Author(s):  
Ci Fu ◽  
Aaliyah Davy ◽  
Simeon Holmes ◽  
Sheng Sun ◽  
Vikas Yadav ◽  
...  
Keyword(s):  
Fungal Pathogen ◽  
Copy Number ◽  
Molecular Mechanisms ◽  
Chromosome Instability ◽  
Human Fungal Pathogen ◽  
Unisexual Reproduction ◽  
Genes Encoding ◽  
Dynamic Genome ◽  
Selection For ◽  
Regulator Genes

Genome copy number variation occurs during each mitotic and meiotic cycle and it is crucial for organisms to maintain their natural ploidy. Defects in ploidy transitions can lead to chromosome instability, which is a hallmark of cancer. Ploidy in the haploid human fungal pathogen Cryptococcus neoformans is exquisitely orchestrated and ranges from haploid to polyploid during sexual development and under various environmental and host conditions. However, the mechanisms controlling these ploidy transitions are largely unknown. During C. deneoformans (formerly C. neoformans var. neoformans, serotype D) unisexual reproduction, ploidy increases prior to the onset of meiosis, can be independent from cell-cell fusion and nuclear fusion, and likely occurs through an endoreplication pathway. To elucidate the molecular mechanisms underlying this ploidy transition, we identified twenty cell cycle-regulating genes encoding cyclins, cyclin-dependent kinases (CDK), and CDK regulators. We characterized four cyclin genes and two CDK regulator genes that were differentially expressed during unisexual reproduction and contributed to diploidization. To detect ploidy transition events, we generated a ploidy reporter, called NURAT, which can detect copy number increases via double selection for nourseothricin-resistant, uracil-prototrophic cells. Utilizing this ploidy reporter, we showed that ploidy transition from haploid to diploid can be detected during the early phases of unisexual reproduction. Interestingly, selection for the NURAT reporter revealed several instances of segmental aneuploidy of multiple chromosomes, which conferred azole resistance in some isolates. These findings provide further evidence of ploidy plasticity in fungi with significant biological and public health implications.

scholarly journals Molecular Mechanisms of Hypoxic Responses via Unique Roles of Ras1, Cdc24 and Ptp3 in a Human Fungal Pathogen Cryptococcus neoformans

PLoS Genetics ◽  
2014 ◽  
Vol 10 (4) ◽  
pp. e1004292 ◽  
Author(s):  
Yun C. Chang ◽  
Ami Khanal Lamichhane ◽  
H. Martin Garraffo ◽  
Peter J. Walter ◽  
Maarten Leerkes ◽  
...  
Keyword(s):  
Cryptococcus Neoformans ◽  
Fungal Pathogen ◽  
Molecular Mechanisms ◽  
Human Fungal Pathogen

scholarly journals Tolerance to fluconazole in Candida albicans is regulated by temperature and aneuploidy

2021 ◽  
Vol 3 (12) ◽  
Author(s):  
FENG YANG ◽  
YUANYING JIANG ◽  
JUDITH BERMAN
Keyword(s):  
Candida Albicans ◽  
High Temperature ◽  
Fungal Pathogen ◽  
Drug Tolerance ◽  
Antifungal Drugs ◽  
Clinical Isolates ◽  
Human Fungal Pathogen ◽  
Genes Encoding ◽  
Aneuploid Chromosome ◽  
Definition Of

Candida albicans is a prevalent human fungal pathogen. Azoles are the most widely used antifungal drugs. Drug tolerance in bacteria is well defined and thoroughly studied, but in fungi, the definition of drug tolerance and the mechanism that drive it are not well understood. Here, we found that a large proportion of clinical isolates were intrinsically tolerant to fluconazole, and/or could be induced by high temperature (37°C) to become tolerant (conditionally tolerant). When treated with inhibitory doses of fluconazole, non-tolerant strains became tolerant by forming aneuploids involving different chromosomes, with chromosome R duplication as the most recurrent mechanism. Tolerance determines the ability to grow in the presence of fluconazole and other azoles, in a manner independent of the MIC. Both temperature conditional tolerance and the associated aneuploidy were sensitive to FK506, an inhibitor of calcineurin. Intrinsic and conditional tolerance were also abolished by deletions of genes encoding the calcineurin (CMP1 and CNB1). However, the dependence of tolerance on calcineurin could be bypassed by a different aneuploid chromosome. Thus, fluconazole tolerance in C. albicans is regulated by temperature and by aneuploidy and is dependent upon aneuploidy, but this dependence can be bypassed by an additional aneuploidy.

The Ess1 prolyl isomerase is dispensable for growth but required for virulence in Cryptococcus neoformans

Microbiology ◽  
2005 ◽  
Vol 151 (5) ◽  
pp. 1593-1605 ◽  
Author(s):  
Ping Ren ◽  
Anne Rossettini ◽  
Vishnu Chaturvedi ◽  
Steven D. Hanes
Keyword(s):  
Rna Polymerase Ii ◽  
Cryptococcus Neoformans ◽  
Fungal Pathogen ◽  
Virulence Genes ◽  
Prolyl Isomerase ◽  
Human Fungal Pathogen ◽  
Genes Encoding ◽  
Urease Production ◽  
Fk506 Binding Proteins

Cryptococcus neoformans is an important human fungal pathogen that also serves as a model for studies of fungal pathogenesis. C. neoformans contains several genes encoding peptidyl-prolyl cis/trans isomerases (PPIases), enzymes that catalyse changes in the folding and conformation of target proteins. Three distinct classes of PPIases have been identified: cyclophilins, FK506-binding proteins (FKBPs) and parvulins. This paper reports the cloning and characterization of ESS1, which is believed to be the first (and probably only) parvulin-class PPIase in C. neoformans. It is shown that ESS1 from C. neoformans is structurally and functionally homologous to ESS1 from Saccharomyces cerevisiae, which encodes an essential PPIase that interacts with RNA polymerase II and plays a role in transcription. In C. neoformans, ESS1 was found to be dispensable for growth, haploid fruiting and capsule formation. However, ESS1 was required for virulence in a murine model of cryptococcosis. Loss of virulence might have been due to the defects in melanin and urease production observed in ess1 mutants, or to defects in transcription of as-yet-unidentified virulence genes. The fact that Ess1 is not essential in C. neoformans suggests that, in this organism, some of its functions might be subsumed by other prolyl isomerases, in particular, cyclophilins Cpa1 or Cpa2. This is supported by the finding that ess1 mutants were hypersensitive to cyclosporin A. C. neoformans might therefore be a useful organism in which to investigate crosstalk among different families of prolyl isomerases.

scholarly journals The Dynamic Genome and Transcriptome of the Human Fungal Pathogen Blastomyces and Close Relative Emmonsia

PLoS Genetics ◽  
2015 ◽  
Vol 11 (10) ◽  
pp. e1005493 ◽  
Author(s):  
José F. Muñoz ◽  
Gregory M. Gauthier ◽  
Christopher A. Desjardins ◽  
Juan E. Gallo ◽  
Jason Holder ◽  
...  
Keyword(s):  
Fungal Pathogen ◽  
Close Relative ◽  
Human Fungal Pathogen ◽  
Dynamic Genome

scholarly journals Survival-Critical Genes Associated with Copy Number Alterations in Lung Adenocarcinoma

Cancers ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 2586
Author(s):  
Chinthalapally V. Rao ◽  
Chao Xu ◽  
Mudassir Farooqui ◽  
Yuting Zhang ◽  
Adam S. Asch ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Copy Number ◽  
Chromosome Instability ◽  
Surrogate Marker ◽  
Copy Number Alterations ◽  
Critical Pathways ◽  
Regulator Genes ◽  
Surveillance Mechanism ◽  
Broad Role

Chromosome Instability (CIN) in tumors affects carcinogenesis, drug resistance, and recurrence/prognosis. Thus, it has a high impact on outcomes in clinic. However, how CIN occurs in human tumors remains elusive. Although cells with CIN (i.e., pre/early cancer cells) are proposed to be removed by apoptosis and/or a surveillance mechanism, this surveillance mechanism is poorly understood. Here we employed a novel data-mining strategy (Gene Expression to Copy Number Alterations [CNA]; “GE-CNA”) to comprehensively identify 1578 genes that associate with CIN, indicated by genomic CNA as its surrogate marker, in human lung adenocarcinoma. We found that (a) amplification/insertion CNA is facilitated by over-expressions of DNA replication stressor and suppressed by a broad range of immune cells (T-, B-, NK-cells, leukocytes), and (b) deletion CNA is facilitated by over-expressions of mitotic regulator genes and suppressed predominantly by leukocytes guided by leukocyte extravasation signaling. Among the 39 CNA- and survival-associated genes, the purine metabolism (PPAT, PAICS), immune-regulating CD4-LCK-MEC2C and CCL14-CCR1 axes, and ALOX5 emerged as survival-critical pathways. These findings revealed a broad role of the immune system in suppressing CIN/CNA and cancer development in lung, and identified components representing potential targets for future chemotherapy, chemoprevention, and immunomodulation approaches for lung adenocarcinoma.

scholarly journals A Transcriptomics Approach To Unveiling the Mechanisms ofIn VitroEvolution towards Fluconazole Resistance of aCandida glabrataClinical Isolate

2018 ◽  
Vol 63 (1) ◽  
Author(s):  
Mafalda Cavalheiro ◽  
Catarina Costa ◽  
Ana Silva-Dias ◽  
Isabel M. Miranda ◽  
Can Wang ◽  
...  
Keyword(s):  
Fungal Pathogen ◽  
Biofilm Formation ◽  
Molecular Mechanisms ◽  
Antifungal Drugs ◽  
Azole Resistance ◽  
Fluconazole Resistance ◽  
Content Type ◽  
Antifungal Drug Resistance ◽  
Genes Encoding ◽  
Multidrug Resistance Transporters

ABSTRACTCandida glabratais an emerging fungal pathogen. Its increased prevalence is associated with its ability to rapidly develop antifungal drug resistance, particularly to azoles. In order to unravel new molecular mechanisms behind azole resistance, a transcriptomics analysis of the evolution of aC. glabrataclinical isolate (isolate 044) from azole susceptibility to posaconazole resistance (21st day), clotrimazole resistance (31st day), and fluconazole and voriconazole resistance (45th day), induced by longstanding incubation with fluconazole, was carried out. All the evolved strains were found to accumulate lower concentrations of azole drugs than the parental strain, while the ergosterol concentration remained mostly constant. However, only the population displaying resistance to all azoles was found to have a gain-of-function mutation in theC. glabrataPDR1gene, leading to the upregulation of genes encoding multidrug resistance transporters. Intermediate strains, exhibiting posaconazole/clotrimazole resistance and increased fluconazole/voriconazole MIC levels, were found to display alternative ways to resist azole drugs. Particularly, posaconazole/clotrimazole resistance after 31 days was correlated with increased expression of adhesin genes. This finding led us to identify the Epa3 adhesin as a new determinant of azole resistance. Besides being required for biofilm formation, Epa3 expression was found to decrease the intracellular accumulation of azole antifungal drugs. Altogether, this work provides a glimpse of the transcriptomics evolution of aC. glabratapopulation toward multiazole resistance, highlighting the multifactorial nature of the acquisition of azole resistance and pointing out a new player in azole resistance.

scholarly journals Metabolome and transcriptome analyses of the molecular mechanisms of flower color mutation in tobacco

BMC Genomics ◽  
2020 ◽  
Vol 21 (1) ◽  
Author(s):  
Fangchan Jiao ◽  
Lu Zhao ◽  
Xingfu Wu ◽  
Zhongbang Song ◽  
Yongping Li
Keyword(s):  
Molecular Mechanisms ◽  
Flower Color ◽  
Syringic Acid ◽  
Structural Genes ◽  
Genes Encoding ◽  
Color Mutation ◽  
Regulation Mechanisms ◽  
Transcriptome Analyses ◽  
Regulator Genes ◽  
Bhlh Transcription Factors

Abstract Background Anthocyanins determinate the flower color of many plants. Tobacco is a model plant for studying the molecular regulation of flower coloration. We investigated the mechanism underlying flower coloration in tobacco by profiling flavonoid metabolites,expression of anthocyanin biosynthetic structural genes and their regulator genes in the pink-flowered tobacco cultivar Yunyan 87 and white-flowered Yunyan 87 mutant. Result Significant down-accumulation of anthocyanins, including cyanidin 3-O-glucoside, cyanin, cyanidin 3-O-rutinoside, pelargonidin 3-O-beta-D-glucoside, cyanidin O-syringic acid, pelargonin, and pelargonidin 3-O-malonylhexoside (log2 fold change < − 10), endowed the flower color mutation in Yunyan 87 mutant. Transcriptome analysis showed that the coordinately down-regulated anthocyanin biosynthetic genes including chalcone isomerase, naringenin 3-dioxygenase, dihydroflavonol 4-reductase and UDP-glucose:flavonoid 3-O-glucosyltransferase played critical roles in suppressing the formation of the aforesaid anthocyanins. Several genes encoding MYB and bHLH transcription factors were also found down-regulated, and probably the reason for the suppression of structural genes. Conclusion This is the first study of tobacco flower coloration combining metabolome and transcriptome analyses, and the results shed a light on the systematic regulation mechanisms of flower coloration in tobacco. The obtained information will aid in developing strategies to modify flower color through genetic transformation.

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