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Search Results: 1 - 10 of 214246 matches for " Alexander D. Johnson "
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Differential Phagocytosis of White versus Opaque Candida albicans by Drosophila and Mouse Phagocytes
Matthew B. Lohse, Alexander D. Johnson
PLOS ONE , 2008, DOI: 10.1371/journal.pone.0001473
Abstract: The human fungal pathogen Candida albicans resides asymptomatically in the gut of most healthy people but causes serious invasive diseases in immunocompromised patients. Many C. albicans strains have the ability to stochastically switch between distinct white and opaque cell types, but it is not known with certainty what role this switching plays in the physiology of the organism. Here, we report a previously undescribed difference between white and opaque cells, namely their interaction with host phagocytic cells. We show that both Drosophila hemocyte-derived S2 cells and mouse macrophage-derived RAW264.7 cells preferentially phagocytose white cells over opaque cells. This difference is seen both in the overall percentage of cultured cells that phagocytose white versus opaque C. albicans and in the average number of C. albicans taken up by each phagocytic cell. We conclude that susceptibility to phagocytosis by cells of the innate immune system is an important distinction between white and opaque C. albicans, and propose that one role of switching from the prevalent white form into the rarer opaque form may be to allow C. albicans to escape phagocytosis.
MochiView: versatile software for genome browsing and DNA motif analysis
Oliver R Homann, Alexander D Johnson
BMC Biology , 2010, DOI: 10.1186/1741-7007-8-49
Abstract: We present MochiView, a platform-independent Java software that integrates browsing of genomic sequences, features, and data with DNA motif visualization and analysis in a visually-appealing and user-friendly application.While highly versatile, the software is particularly useful for organizing, exploring, and analyzing large genomic data sets, such as those from deep RNA sequencing, chromatin immunoprecipitation experiments (ChIP-Seq and ChIP-Chip), and transcriptional profiling. MochiView provides an extensive suite of utilities to identify and to explore connections between these data sets and short sequence motifs present in DNA or RNA.We describe a versatile tool for visualizing and exploring large genomic data sets, particularly those generated by chromatin immunoprecipitation (ChIP). This technique is often used to identify regions of a genome that are bound by a specific transcription factor under a given set of conditions. For those transcription factors that recognize DNA directly, it is often possible, from ChIP data alone, to deduce the range of DNA sequences (the motif) that a given transcription factor recognizes. ChIP relies on cross-linking transcription factors to DNA in living cells, shearing and isolating the DNA, and recovering the DNA cross-linked to a specific transcription factor. The recovered DNA is then analyzed using either tiling microarrays (ChIP-Chip) or sequencing (ChIP-Seq). Both approaches generate a nearly continuous profile of binding enrichment across the genome, with high-density tiling for ChIP-Chip currently being feasible only for smaller genomes, such as those from bacteria or fungi. Several existing genome browsers aid in the visualization and analysis of such data, but few contain tools to easily integrate motif data into the analysis. MochiView (Motif and ChIP Viewer) is designed to bridge this gap, providing a highly flexible and intuitive interface that allows one to easily import, visualize, explore, and analyze large s
Regulatory Circuits That Enable Proliferation of the Fungus Candida albicans in a Mammalian Host
J. Christian Pérez ,Alexander D. Johnson
PLOS Pathogens , 2013, DOI: 10.1371/journal.ppat.1003780
Candida albicans Commensalism and Pathogenicity Are Intertwined Traits Directed by a Tightly Knit Transcriptional Regulatory Circuit
J. Christian Pérez ,Carol A. Kumamoto,Alexander D. Johnson
PLOS Biology , 2013, DOI: 10.1371/journal.pbio.1001510
Abstract: Systemic, life-threatening infections in humans are often caused by bacterial or fungal species that normally inhabit a different locale in our body, particularly mucosal surfaces. A hallmark of these opportunistic pathogens, therefore, is their ability to thrive in disparate niches within the host. In this work, we investigate the transcriptional circuitry and gene repertoire that enable the human opportunistic fungal pathogen Candida albicans to proliferate in two different niches. By screening a library of transcription regulator deletion strains in mouse models of intestinal colonization and systemic infection, we identified eight transcription regulators that play roles in at least one of these models. Using genome-wide chromatin immunoprecipitation, we uncovered a network comprising ~800 target genes and a tightly knit transcriptional regulatory circuit at its core. The network is enriched with genes upregulated in C. albicans cells growing in the host. Our findings indicate that many aspects of commensalism and pathogenicity are intertwined and that the ability of this microorganism to colonize multiple niches relies on a large, integrated circuit.
The Evolution of Combinatorial Gene Regulation in Fungi
Brian B. Tuch,David J. Galgoczy,Aaron D. Hernday,Hao Li,Alexander D. Johnson
PLOS Biology , 2012, DOI: 10.1371/journal.pbio.0060038
Abstract: It is widely suspected that gene regulatory networks are highly plastic. The rapid turnover of transcription factor binding sites has been predicted on theoretical grounds and has been experimentally demonstrated in closely related species. We combined experimental approaches with comparative genomics to focus on the role of combinatorial control in the evolution of a large transcriptional circuit in the fungal lineage. Our study centers on Mcm1, a transcriptional regulator that, in combination with five cofactors, binds roughly 4% of the genes in Saccharomyces cerevisiae and regulates processes ranging from the cell-cycle to mating. In Kluyveromyces lactis and Candida albicans, two other hemiascomycetes, we find that the Mcm1 combinatorial circuits are substantially different. This massive rewiring of the Mcm1 circuitry has involved both substantial gain and loss of targets in ancient combinatorial circuits as well as the formation of new combinatorial interactions. We have dissected the gains and losses on the global level into subsets of functionally and temporally related changes. One particularly dramatic change is the acquisition of Mcm1 binding sites in close proximity to Rap1 binding sites at 70 ribosomal protein genes in the K. lactis lineage. Another intriguing and very recent gain occurs in the C. albicans lineage, where Mcm1 is found to bind in combination with the regulator Wor1 at many genes that function in processes associated with adaptation to the human host, including the white-opaque epigenetic switch. The large turnover of Mcm1 binding sites and the evolution of new Mcm1–cofactor interactions illuminate in sharp detail the rapid evolution of combinatorial transcription networks.
Candida albicans White and Opaque Cells Undergo Distinct Programs of Filamentous Growth
Haoyu Si,Aaron D. Hernday,Matthew P. Hirakawa,Alexander D. Johnson,Richard J. Bennett
PLOS Pathogens , 2013, DOI: 10.1371/journal.ppat.1003210
Abstract: The ability to switch between yeast and filamentous forms is central to Candida albicans biology. The yeast-hyphal transition is implicated in adherence, tissue invasion, biofilm formation, phagocyte escape, and pathogenesis. A second form of morphological plasticity in C. albicans involves epigenetic switching between white and opaque forms, and these two states exhibit marked differences in their ability to undergo filamentation. In particular, filamentous growth in white cells occurs in response to a number of environmental conditions, including serum, high temperature, neutral pH, and nutrient starvation, whereas none of these stimuli induce opaque filamentation. Significantly, however, we demonstrate that opaque cells can undergo efficient filamentation but do so in response to distinct environmental cues from those that elicit filamentous growth in white cells. Growth of opaque cells in several environments, including low phosphate medium and sorbitol medium, induced extensive filamentous growth, while white cells did not form filaments under these conditions. Furthermore, while white cell filamentation is often enhanced at elevated temperatures such as 37°C, opaque cell filamentation was optimal at 25°C and was inhibited by higher temperatures. Genetic dissection of the opaque filamentation pathway revealed overlapping regulation with the filamentous program in white cells, including key roles for the transcription factors EFG1, UME6, NRG1 and RFG1. Gene expression profiles of filamentous white and opaque cells were also compared and revealed only limited overlap between these programs, although UME6 was induced in both white and opaque cells consistent with its role as master regulator of filamentation. Taken together, these studies establish that a program of filamentation exists in opaque cells. Furthermore, this program regulates a distinct set of genes and is under different environmental controls from those operating in white cells.
An RNA Transport System in Candida albicans Regulates Hyphal Morphology and Invasive Growth
Sarah L. Elson,Suzanne M. Noble,Norma V. Solis,Scott G. Filler,Alexander D. Johnson
PLOS Genetics , 2009, DOI: 10.1371/journal.pgen.1000664
Abstract: Localization of specific mRNAs is an important mechanism through which cells achieve polarity and direct asymmetric growth. Based on a framework established in Saccharomyces cerevisiae, we describe a She3-dependent RNA transport system in Candida albicans, a fungal pathogen of humans that grows as both budding (yeast) and filamentous (hyphal and pseudohyphal) forms. We identify a set of 40 mRNAs that are selectively transported to the buds of yeast-form cells and to the tips of hyphae, and we show that many of the genes encoded by these mRNAs contribute to hyphal development, as does the transport system itself. Although the basic system of mRNA transport is conserved between S. cerevisiae and C. albicans, we find that the cargo mRNAs have diverged considerably, implying that specific mRNAs can easily move in and out of transport control over evolutionary timescales. The differences in mRNA cargos likely reflect the distinct selective pressures acting on the two species.
A Phenotypic Profile of the Candida albicans Regulatory Network
Oliver R. Homann ,Jeanselle Dea,Suzanne M. Noble,Alexander D. Johnson
PLOS Genetics , 2009, DOI: 10.1371/journal.pgen.1000783
Abstract: Candida albicans is a normal resident of the gastrointestinal tract and also the most prevalent fungal pathogen of humans. It last shared a common ancestor with the model yeast Saccharomyces cerevisiae over 300 million years ago. We describe a collection of 143 genetically matched strains of C. albicans, each of which has been deleted for a specific transcriptional regulator. This collection represents a large fraction of the non-essential transcription circuitry. A phenotypic profile for each mutant was developed using a screen of 55 growth conditions. The results identify the biological roles of many individual transcriptional regulators; for many, this work represents the first description of their functions. For example, a quarter of the strains showed altered colony formation, a phenotype reflecting transitions among yeast, pseudohyphal, and hyphal cell forms. These transitions, which have been closely linked to pathogenesis, have been extensively studied, yet our work nearly doubles the number of transcriptional regulators known to influence them. As a second example, nearly a quarter of the knockout strains affected sensitivity to commonly used antifungal drugs; although a few transcriptional regulators have previously been implicated in susceptibility to these drugs, our work indicates many additional mechanisms of sensitivity and resistance. Finally, our results inform how transcriptional networks evolve. Comparison with the existing S. cerevisiae data (supplemented by additional S. cerevisiae experiments reported here) allows the first systematic analysis of phenotypic conservation by orthologous transcriptional regulators over a large evolutionary distance. We find that, despite the many specific wiring changes documented between these species, the general phenotypes of orthologous transcriptional regulator knockouts are largely conserved. These observations support the idea that many wiring changes affect the detailed architecture of the circuit, but not its overall output.
Interlocking Transcriptional Feedback Loops Control White-Opaque Switching in Candida albicans
Rebecca E. Zordan,Mathew G. Miller,David J. Galgoczy,Brian B. Tuch,Alexander D. Johnson
PLOS Biology , 2012, DOI: 10.1371/journal.pbio.0050256
Abstract: The human pathogen Candida albicans can assume either of two distinct cell types, designated “white” and “opaque.” Each cell type is maintained for many generations; switching between them is rare and stochastic, and occurs without any known changes in the nucleotide sequence of the genome. The two cell types differ dramatically in cell shape, colony appearance, mating competence, and virulence properties. In this work, we investigate the transcriptional circuitry that specifies the two cell types and controls the switching between them. First, we identify two new transcriptional regulators of white-opaque switching, Czf1 and white-opaque regulator 2 (Wor2). Analysis of a large set of double mutants and ectopic expression strains revealed genetic relationships between CZF1, WOR2, and two previously identified regulators of white-opaque switching, WOR1 and EFG1. Using chromatin immunoprecipitation, we show that Wor1 binds the intergenic regions upstream of the genes encoding three additional transcriptional regulators of white-opaque switching (CZF1, EFG1, and WOR2), and also occupies the promoters of numerous white- and opaque-enriched genes. Based on these interactions, we have placed these four genes in a circuit controlling white-opaque switching whose topology is a network of positive feedback loops, with the master regulator gene WOR1 occupying a central position. Our observations indicate that a key role of the interlocking feedback loop network is to stably maintain each epigenetic state through many cell divisions.
The Parasexual Cycle in Candida albicans Provides an Alternative Pathway to Meiosis for the Formation of Recombinant Strains
Anja Forche,Kevin Alby,Dana Schaefer,Alexander D. Johnson,Judith Berman,Richard J. Bennett
PLOS Biology , 2012, DOI: 10.1371/journal.pbio.0060110
Abstract: Candida albicans has an elaborate, yet efficient, mating system that promotes conjugation between diploid a and α strains. The product of mating is a tetraploid a/α cell that must undergo a reductional division to return to the diploid state. Despite the presence of several “meiosis-specific” genes in the C. albicans genome, a meiotic program has not been observed. Instead, tetraploid products of mating can be induced to undergo efficient, random chromosome loss, often producing strains that are diploid, or close to diploid, in ploidy. Using SNP and comparative genome hybridization arrays we have now analyzed the genotypes of products from the C. albicans parasexual cycle. We show that the parasexual cycle generates progeny strains with shuffled combinations of the eight C. albicans chromosomes. In addition, several isolates had undergone extensive genetic recombination between homologous chromosomes, including multiple gene conversion events. Progeny strains exhibited altered colony morphologies on laboratory media, demonstrating that the parasexual cycle generates phenotypic variants of C. albicans. In several fungi, including Saccharomyces cerevisiae and Schizosaccharomyces pombe, the conserved Spo11 protein is integral to meiotic recombination, where it is required for the formation of DNA double-strand breaks. We show that deletion of SPO11 prevented genetic recombination between homologous chromosomes during the C. albicans parasexual cycle. These findings suggest that at least one meiosis-specific gene has been re-programmed to mediate genetic recombination during the alternative parasexual life cycle of C. albicans. We discuss, in light of the long association of C. albicans with warm-blooded animals, the potential advantages of a parasexual cycle over a conventional sexual cycle.
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