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Search Results: 1 - 10 of 154598 matches for " Brian B. Tuch equal contributor "
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Interlocking Transcriptional Feedback Loops Control White-Opaque Switching in Candida albicans
Rebecca E Zordan equal contributor,Mathew G Miller equal contributor,David J Galgoczy,Brian B Tuch,Alexander D Johnson
PLOS Biology , 2007, 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 Evolution of Combinatorial Gene Regulation in Fungi
Brian B Tuch equal contributor,David J Galgoczy equal contributor,Aaron D Hernday,Hao Li ,Alexander D Johnson
PLOS Biology , 2008, 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.
The Transcriptomes of Two Heritable Cell Types Illuminate the Circuit Governing Their Differentiation
Brian B. Tuch equal contributor,Quinn M. Mitrovich equal contributor,Oliver R. Homann,Aaron D. Hernday,Cinna K. Monighetti,Francisco M. De La Vega,Alexander D. Johnson
PLOS Genetics , 2010, DOI: 10.1371/journal.pgen.1001070
Abstract: The differentiation of cells into distinct cell types, each of which is heritable for many generations, underlies many biological phenomena. White and opaque cells of the fungal pathogen Candida albicans are two such heritable cell types, each thought to be adapted to unique niches within their human host. To systematically investigate their differences, we performed strand-specific, massively-parallel sequencing of RNA from C. albicans white and opaque cells. With these data we first annotated the C. albicans transcriptome, finding hundreds of novel differentially-expressed transcripts. Using the new annotation, we compared differences in transcript abundance between the two cell types with the genomic regions bound by a master regulator of the white-opaque switch (Wor1). We found that the revised transcriptional landscape considerably alters our understanding of the circuit governing differentiation. In particular, we can now resolve the poor concordance between binding of a master regulator and the differential expression of adjacent genes, a discrepancy observed in several other studies of cell differentiation. More than one third of the Wor1-bound differentially-expressed transcripts were previously unannotated, which explains the formerly puzzling presence of Wor1 at these positions along the genome. Many of these newly identified Wor1-regulated genes are non-coding and transcribed antisense to coding transcripts. We also find that 5′ and 3′ UTRs of mRNAs in the circuit are unusually long and that 5′ UTRs often differ in length between cell-types, suggesting UTRs encode important regulatory information and that use of alternative promoters is widespread. Further analysis revealed that the revised Wor1 circuit bears several striking similarities to the Oct4 circuit that specifies the pluripotency of mammalian embryonic stem cells. Additional characteristics shared with the Oct4 circuit suggest a set of general hallmarks characteristic of heritable differentiation states in eukaryotes.
Crossing the Line: Selection and Evolution of Virulence Traits
Nat F Brown equal contributor,Mark E Wickham equal contributor,Brian K Coombes,B. Brett Finlay
PLOS Pathogens , 2006, DOI: 10.1371/journal.ppat.0020042
Abstract: The evolution of pathogens presents a paradox. Pathogenic species are often absolutely dependent on their host species for their propagation through evolutionary time, yet the pathogenic lifestyle requires that the host be damaged during this dependence. It is clear that pathogenic strategies are successful in evolutionary terms because a diverse array of pathogens exists in nature. Pathogens also evolve using a broad range of molecular mechanisms to acquire and modulate existing virulence traits in order to achieve this success. Detailing the benefit of enhanced selection derived through virulence and understanding the mechanisms through which virulence evolves are important to understanding the natural world and both have implications for human health.
Fine-Mapping the HOXB Region Detects Common Variants Tagging a Rare Coding Allele: Evidence for Synthetic Association in Prostate Cancer
Edward J. Saunders,Tokhir Dadaev,Daniel A. Leongamornlert,Sarah Jugurnauth-Little,Malgorzata Tymrakiewicz,Fredrik Wiklund,Ali Amin Al Olama,Sara Benlloch,David E. Neal equal contributor,Freddie C. Hamdy equal contributor,Jenny L. Donovan equal contributor,Graham G. Giles equal contributor,Gianluca Severi equal contributor,Henrik Gronberg equal contributor,Markus Aly equal contributor,Christopher A. Haiman equal contributor,Fredrick Schumacher equal contributor,Brian E. Henderson equal contributor,Sara Lindstrom equal contributor,Peter Kraft equal contributor,David J. Hunter equal contributor,Susan Gapstur equal contributor,Stephen Chanock equal contributor,Sonja I. Berndt equal contributor,Demetrius Albanes equal contributor,Gerald Andriole equal contributor,Johanna Schleutker equal contributor,Maren Weischer equal contributor,B?rge G. Nordestgaard equal contributor,Federico Canzian equal contributor,Daniele Campa equal contributor,Elio Riboli equal contributor,Tim J. Key equal contributor,Ruth C. Travis equal contributor,Sue A. Ingles equal contributor,Esther M. John equal contributor,Richard B. Hayes equal contributor,Paul Pharoah equal contributor,Kay-Tee Khaw equal contributor,Janet L. Stanford equal contributor,Elaine A. Ostrander equal contributor,Lisa B. Signorello equal contributor,Stephen N. Thibodeau equal contributor,Daniel Schaid equal contributor,Christiane Maier equal contributor,Adam S. Kibel equal contributor,Cezary Cybulski equal contributor
PLOS Genetics , 2014, DOI: doi/10.1371/journal.pgen.1004129
Abstract: The HOXB13 gene has been implicated in prostate cancer (PrCa) susceptibility. We performed a high resolution fine-mapping analysis to comprehensively evaluate the association between common genetic variation across the HOXB genetic locus at 17q21 and PrCa risk. This involved genotyping 700 SNPs using a custom Illumina iSelect array (iCOGS) followed by imputation of 3195 SNPs in 20,440 PrCa cases and 21,469 controls in The PRACTICAL consortium. We identified a cluster of highly correlated common variants situated within or closely upstream of HOXB13 that were significantly associated with PrCa risk, described by rs117576373 (OR 1.30, P = 2.62×10?14). Additional genotyping, conditional regression and haplotype analyses indicated that the newly identified common variants tag a rare, partially correlated coding variant in the HOXB13 gene (G84E, rs138213197), which has been identified recently as a moderate penetrance PrCa susceptibility allele. The potential for GWAS associations detected through common SNPs to be driven by rare causal variants with higher relative risks has long been proposed; however, to our knowledge this is the first experimental evidence for this phenomenon of synthetic association contributing to cancer susceptibility.
Salmonella Pathogenicity Island 2 Is Expressed Prior to Penetrating the Intestine
Nat F Brown equal contributor,Bruce A Vallance equal contributor,Brian K Coombes,Yanet Valdez,Bryan A Coburn,B. Brett Finlay
PLOS Pathogens , 2005, DOI: 10.1371/journal.ppat.0010032
Abstract: Salmonella enterica serovar Typhimurium is a facultative intracellular pathogen that causes disease in mice that resembles human typhoid. Typhoid pathogenesis consists of distinct phases in the intestine and a subsequent systemic phase in which bacteria replicate in macrophages of the liver and spleen. The type III secretion system encoded by Salmonella pathogenicity island 2 (SPI-2) is a major virulence factor contributing to the systemic phase of typhoid pathogenesis. Understanding how pathogens regulate virulence mechanisms in response to the environment, including different host tissues, is key to our understanding of pathogenesis. A recombinase-based in vivo expression technology system was developed to assess SPI-2 expression during murine typhoid. SPI-2 expression was detectable at very early times in bacteria that were resident in the lumen of the ileum and was independent of active bacterial invasion of the epithelium. We also provide direct evidence for the regulation of SPI-2 by the Salmonella transcription factors ompR and ssrB in vivo. Together these results demonstrate that SPI-2 expression precedes penetration of the intestinal epithelium. This induction of expression precedes any documented SPI-2-dependent phases of typhoid and may be involved in preparing Salmonella to successfully resist the antimicrobial environment encountered within macrophages.
Viral OTU Deubiquitinases: A Structural and Functional Comparison
Ben A. Bailey-Elkin equal contributor,Puck B. van Kasteren equal contributor,Eric J. Snijder,Marjolein Kikkert ? ,Brian L. Mark ?
PLOS Pathogens , 2014, DOI: doi/10.1371/journal.ppat.1003894
Abstract: Recent studies have revealed that proteases encoded by three very diverse RNA virus groups share structural similarity with enzymes of the Ovarian Tumor (OTU) superfamily of deubiquitinases (DUBs). The publication of the latest of these reports in quick succession prevented proper recognition and discussion of the shared features of these viral enzymes. Here we provide a brief structural and functional comparison of these virus-encoded OTU DUBs. Interestingly, although their shared structural features and substrate specificity tentatively place them within the same protease superfamily, they also show interesting differences that trigger speculation as to their origins.
Genomic Analysis of the Hydrocarbon-Producing, Cellulolytic, Endophytic Fungus Ascocoryne sarcoides
Tara A. Gianoulis equal contributor,Meghan A. Griffin equal contributor,Daniel J. Spakowicz equal contributor,Brian F. Dunican,Cambria J. Alpha,Andrea Sboner,A. Michael Sismour,Chinnappa Kodira,Michael Egholm,George M. Church,Mark B. Gerstein ,Scott A. Strobel
PLOS Genetics , 2012, DOI: 10.1371/journal.pgen.1002558
Abstract: The microbial conversion of solid cellulosic biomass to liquid biofuels may provide a renewable energy source for transportation fuels. Endophytes represent a promising group of organisms, as they are a mostly untapped reservoir of metabolic diversity. They are often able to degrade cellulose, and they can produce an extraordinary diversity of metabolites. The filamentous fungal endophyte Ascocoryne sarcoides was shown to produce potential-biofuel metabolites when grown on a cellulose-based medium; however, the genetic pathways needed for this production are unknown and the lack of genetic tools makes traditional reverse genetics difficult. We present the genomic characterization of A. sarcoides and use transcriptomic and metabolomic data to describe the genes involved in cellulose degradation and to provide hypotheses for the biofuel production pathways. In total, almost 80 biosynthetic clusters were identified, including several previously found only in plants. Additionally, many transcriptionally active regions outside of genes showed condition-specific expression, offering more evidence for the role of long non-coding RNA in gene regulation. This is one of the highest quality fungal genomes and, to our knowledge, the only thoroughly annotated and transcriptionally profiled fungal endophyte genome currently available. The analyses and datasets contribute to the study of cellulose degradation and biofuel production and provide the genomic foundation for the study of a model endophyte system.
TGF-b2 Induction Regulates Invasiveness of Theileria-Transformed Leukocytes and Disease Susceptibility
Marie Chaussepied equal contributor,Natacha Janski equal contributor,Martin Baumgartner equal contributor,Regina Lizundia ?,Kirsty Jensen ?,William Weir,Brian R. Shiels,Jonathan B. Weitzman,Elizabeth J. Glass,Dirk Werling,Gordon Langsley
PLOS Pathogens , 2010, DOI: 10.1371/journal.ppat.1001197
Abstract: Theileria parasites invade and transform bovine leukocytes causing either East Coast fever (T. parva), or tropical theileriosis (T. annulata). Susceptible animals usually die within weeks of infection, but indigenous infected cattle show markedly reduced pathology, suggesting that host genetic factors may cause disease susceptibility. Attenuated live vaccines are widely used to control tropical theileriosis and attenuation is associated with reduced invasiveness of infected macrophages in vitro. Disease pathogenesis is therefore linked to aggressive invasiveness, rather than uncontrolled proliferation of Theileria-infected leukocytes. We show that the invasive potential of Theileria-transformed leukocytes involves TGF-b signalling. Attenuated live vaccine lines express reduced TGF-b2 and their invasiveness can be rescued with exogenous TGF-b. Importantly, infected macrophages from disease susceptible Holstein-Friesian (HF) cows express more TGF-b2 and traverse Matrigel with great efficiency compared to those from disease-resistant Sahiwal cattle. Thus, TGF-b2 levels correlate with disease susceptibility. Using fluorescence and time-lapse video microscopy we show that Theileria-infected, disease-susceptible HF macrophages exhibit increased actin dynamics in their lamellipodia and podosomal adhesion structures and develop more membrane blebs. TGF-b2-associated invasiveness in HF macrophages has a transcription-independent element that relies on cytoskeleton remodelling via activation of Rho kinase (ROCK). We propose that a TGF-b autocrine loop confers an amoeboid-like motility on Theileria-infected leukocytes, which combines with MMP-dependent motility to drive invasiveness and virulence.
Enterohemorrhagic E. coli Requires N-WASP for Efficient Type III Translocation but Not for EspFU-Mediated Actin Pedestal Formation
Didier Vingadassalom equal contributor,Kenneth G. Campellone equal contributor,Michael J. Brady,Brian Skehan,Scott E. Battle,Douglas Robbins,Archana Kapoor,Gail Hecht,Scott B. Snapper,John M. Leong
PLOS Pathogens , 2010, DOI: 10.1371/journal.ppat.1001056
Abstract: Upon infection of mammalian cells, enterohemorrhagic E. coli (EHEC) O157:H7 utilizes a type III secretion system to translocate the effectors Tir and EspFU (aka TccP) that trigger the formation of F-actin-rich ‘pedestals’ beneath bound bacteria. EspFU is localized to the plasma membrane by Tir and binds the nucleation-promoting factor N-WASP, which in turn activates the Arp2/3 actin assembly complex. Although N-WASP has been shown to be required for EHEC pedestal formation, the precise steps in the process that it influences have not been determined. We found that N-WASP and actin assembly promote EHEC-mediated translocation of Tir and EspFU into mammalian host cells. When we utilized the related pathogen enteropathogenic E. coli to enhance type III translocation of EHEC Tir and EspFU, we found surprisingly that actin pedestals were generated on N-WASP-deficient cells. Similar to pedestal formation on wild type cells, Tir and EspFU were the only bacterial effectors required for pedestal formation, and the EspFU sequences required to interact with N-WASP were found to also be essential to stimulate this alternate actin assembly pathway. In the absence of N-WASP, the Arp2/3 complex was both recruited to sites of bacterial attachment and required for actin assembly. Our results indicate that actin assembly facilitates type III translocation, and reveal that EspFU, presumably by recruiting an alternate host factor that can signal to the Arp2/3 complex, exhibits remarkable versatility in its strategies for stimulating actin polymerization.
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