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Search Results: 1 - 10 of 9843 matches for " Sara Hardy equal contributor "
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The Euchromatic and Heterochromatic Landscapes Are Shaped by Antagonizing Effects of Transcription on H2A.Z Deposition
Sara Hardy equal contributor,Pierre-étienne Jacques equal contributor,Nicolas Gévry,Audrey Forest,Marie-ève Fortin,Liette Laflamme,Luc Gaudreau,Fran?ois Robert
PLOS Genetics , 2009, DOI: 10.1371/journal.pgen.1000687
Abstract: A role for variant histone H2A.Z in gene expression is now well established but little is known about the mechanisms by which it operates. Using a combination of ChIP–chip, knockdown and expression profiling experiments, we show that upon gene induction, human H2A.Z associates with gene promoters and helps in recruiting the transcriptional machinery. Surprisingly, we also found that H2A.Z is randomly incorporated in the genome at low levels and that active transcription antagonizes this incorporation in transcribed regions. After cessation of transcription, random H2A.Z quickly reappears on genes, demonstrating that this incorporation utilizes an active mechanism. Within facultative heterochromatin, we observe a hyper accumulation of the variant histone, which might be due to the lack of transcription in these regions. These results show how chromatin structure and transcription can antagonize each other, therefore shaping chromatin and controlling gene expression.
Glutamine-Expanded Ataxin-7 Alters TFTC/STAGA Recruitment and Chromatin Structure Leading to Photoreceptor Dysfunction
Dominique Helmlinger,Sara Hardy equal contributor,Gretta Abou-Sleymane equal contributor,Adrien Eberlin,Aaron B Bowman,Anne Gansmüller,Serge Picaud,Huda Y Zoghbi,Yvon Trottier,Làszlò Tora ,Didier Devys
PLOS Biology , 2006, DOI: 10.1371/journal.pbio.0040067
Abstract: Spinocerebellar ataxia type 7 (SCA7) is one of several inherited neurodegenerative disorders caused by a polyglutamine (polyQ) expansion, but it is the only one in which the retina is affected. Increasing evidence suggests that transcriptional alterations contribute to polyQ pathogenesis, although the mechanism is unclear. We previously demonstrated that theSCA7 gene product, ataxin-7 (ATXN7), is a subunit of the GCN5 histone acetyltransferase–containing coactivator complexes TFTC/STAGA. We show here that TFTC/STAGA complexes purified from SCA7 mice have normal TRRAP, GCN5, TAF12, and SPT3 levels and that their histone or nucleosomal acetylation activities are unaffected. However, rod photoreceptors from SCA7 mouse models showed severe chromatin decondensation. In agreement, polyQ-expanded ataxin-7 induced histone H3 hyperacetylation, resulting from an increased recruitment of TFTC/STAGA to specific promoters. Surprisingly, hyperacetylated genes were transcriptionally down-regulated, and expression analysis revealed that nearly all rod-specific genes were affected, leading to visual impairment in SCA7 mice. In conclusion, we describe here a set of events accounting for SCA7 pathogenesis in the retina, in which polyQ-expanded ATXN7 deregulated TFTC/STAGA recruitment to a subset of genes specifically expressed in rod photoreceptors, leading to chromatin alterations and consequent progressive loss of rod photoreceptor function.
Rotavirus NSP1 Inhibits NFκB Activation by Inducing Proteasome-Dependent Degradation of β-TrCP: A Novel Mechanism of IFN Antagonism
Joel W. Graff equal contributor,Khalil Ettayebi equal contributor,Michele E. Hardy
PLOS Pathogens , 2009, DOI: 10.1371/journal.ppat.1000280
Abstract: Mechanisms by which viruses counter innate host defense responses generally involve inhibition of one or more components of the interferon (IFN) system. Multiple steps in the induction and amplification of IFN signaling are targeted for inhibition by viral proteins, and many of the IFN antagonists have direct or indirect effects on activation of latent cytoplasmic transcription factors. Rotavirus nonstructural protein NSP1 blocks transcription of type I IFNα/β by inducing proteasome-dependent degradation of IFN-regulatory factors 3 (IRF3), IRF5, and IRF7. In this study, we show that rotavirus NSP1 also inhibits activation of NFκB and does so by a novel mechanism. Proteasome-mediated degradation of inhibitor of κB (IκBα) is required for NFκB activation. Phosphorylated IκBα is a substrate for polyubiquitination by a multisubunit E3 ubiquitin ligase complex, Skp1/Cul1/F-box, in which the F-box substrate recognition protein is β-transducin repeat containing protein (β-TrCP). The data presented show that phosphorylated IκBα is stable in rotavirus-infected cells because infection induces proteasome-dependent degradation of β-TrCP. NSP1 expressed in isolation in transiently transfected cells is sufficient to induce this effect. Targeted degradation of an F-box protein of an E3 ligase complex with a prominent role in modulation of innate immune signaling and cell proliferation pathways is a unique mechanism of IFN antagonism and defines a second strategy of immune evasion used by rotaviruses.
Identification of a Genomic Reservoir for New TRIM Genes in Primate Genomes
Kyudong Han equal contributor,Dianne I. Lou equal contributor,Sara L. Sawyer
PLOS Genetics , 2011, DOI: 10.1371/journal.pgen.1002388
Abstract: Tripartite Motif (TRIM) ubiquitin ligases act in the innate immune response against viruses. One of the best characterized members of this family, TRIM5α, serves as a potent retroviral restriction factor with activity against HIV. Here, we characterize what are likely to be the youngest TRIM genes in the human genome. For instance, we have identified 11 TRIM genes that are specific to humans and African apes (chimpanzees, bonobos, and gorillas) and another 7 that are human-specific. Many of these young genes have never been described, and their identification brings the total number of known human TRIM genes to approximately 100. These genes were acquired through segmental duplications, most of which originated from a single locus on chromosome 11. Another polymorphic duplication of this locus has resulted in these genes being copy number variable within the human population, with a Han Chinese woman identified as having 12 additional copies of these TRIM genes compared to other individuals screened in this study. Recently, this locus was annotated as one of 34 “hotspot” regions that are also copy number variable in the genomes of chimpanzees and rhesus macaques. Most of the young TRIM genes originating from this locus are expressed, spliced, and contain signatures of positive natural selection in regions known to determine virus recognition in TRIM5α. However, we find that they do not restrict the same retroviruses as TRIM5α, consistent with the high degree of divergence observed in the regions that control target specificity. We propose that this recombinationally volatile locus serves as a reservoir from which new TRIM genes arise through segmental duplication, allowing primates to continually acquire new antiviral genes that can be selected to target new and evolving pathogens.
Integrating Teaching and Research in Undergraduate Biology Laboratory Education
Matthew J. Kloser equal contributor,Sara E. Brownell equal contributor,Nona R. Chiariello,Tadashi Fukami
PLOS Biology , 2011, DOI: 10.1371/journal.pbio.1001174
Inhibition of GSK-3 Ameliorates Aβ Pathology in an Adult-Onset Drosophila Model of Alzheimer's Disease
Oyinkan Sofola equal contributor,Fiona Kerr equal contributor,Iain Rogers equal contributor,Richard Killick,Hrvoje Augustin,Carina Gandy,Marcus J. Allen,John Hardy,Simon Lovestone,Linda Partridge
PLOS Genetics , 2010, DOI: 10.1371/journal.pgen.1001087
Abstract: Aβ peptide accumulation is thought to be the primary event in the pathogenesis of Alzheimer's disease (AD), with downstream neurotoxic effects including the hyperphosphorylation of tau protein. Glycogen synthase kinase-3 (GSK-3) is increasingly implicated as playing a pivotal role in this amyloid cascade. We have developed an adult-onset Drosophila model of AD, using an inducible gene expression system to express Arctic mutant Aβ42 specifically in adult neurons, to avoid developmental effects. Aβ42 accumulated with age in these flies and they displayed increased mortality together with progressive neuronal dysfunction, but in the apparent absence of neuronal loss. This fly model can thus be used to examine the role of events during adulthood and early AD aetiology. Expression of Aβ42 in adult neurons increased GSK-3 activity, and inhibition of GSK-3 (either genetically or pharmacologically by lithium treatment) rescued Aβ42 toxicity. Aβ42 pathogenesis was also reduced by removal of endogenous fly tau; but, within the limits of detection of available methods, tau phosphorylation did not appear to be altered in flies expressing Aβ42. The GSK-3–mediated effects on Aβ42 toxicity appear to be at least in part mediated by tau-independent mechanisms, because the protective effect of lithium alone was greater than that of the removal of tau alone. Finally, Aβ42 levels were reduced upon GSK-3 inhibition, pointing to a direct role of GSK-3 in the regulation of Aβ42 peptide level, in the absence of APP processing. Our study points to the need both to identify the mechanisms by which GSK-3 modulates Aβ42 levels in the fly and to determine if similar mechanisms are present in mammals, and it supports the potential therapeutic use of GSK-3 inhibitors in AD.
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.
Mucosal Immunization with Iron Receptor Antigens Protects against Urinary Tract Infection
Christopher J. Alteri equal contributor,Erin C. Hagan equal contributor,Kelsey E. Sivick equal contributor,Sara N. Smith,Harry L. T. Mobley
PLOS Pathogens , 2009, DOI: 10.1371/journal.ppat.1000586
Abstract: Uncomplicated infections of the urinary tract, caused by uropathogenic Escherichia coli, are among the most common diseases requiring medical intervention. A preventive vaccine to reduce the morbidity and fiscal burden these infections have upon the healthcare system would be beneficial. Here, we describe the results of a large-scale selection process that incorporates bioinformatic, genomic, transcriptomic, and proteomic screens to identify six vaccine candidates from the 5379 predicted proteins encoded by uropathogenic E. coli strain CFT073. The vaccine candidates, ChuA, Hma, Iha, IreA, IroN, and IutA, all belong to a functional class of molecules that is involved in iron acquisition, a process critical for pathogenesis in all microbes. Intranasal immunization of CBA/J mice with these outer membrane iron receptors elicited a systemic and mucosal immune response that included the production of antigen-specific IgM, IgG, and IgA antibodies. The cellular response to vaccination was characterized by the induction and secretion of IFN-γ and IL-17. Of the six potential vaccine candidates, IreA, Hma, and IutA provided significant protection from experimental infection. In immunized animals, class-switching from IgM to IgG and production of antigen-specific IgA in the urine represent immunological correlates of protection from E. coli bladder colonization. These findings are an important first step toward the development of a subunit vaccine to prevent urinary tract infections and demonstrate how targeting an entire class of molecules that are collectively required for pathogenesis may represent a fundamental strategy to combat infections.
CHD3 Proteins and Polycomb Group Proteins Antagonistically Determine Cell Identity in Arabidopsis
Ernst Aichinger equal contributor,Corina B. R. Villar equal contributor,Sara Farrona,José C. Reyes,Lars Hennig,Claudia K?hler
PLOS Genetics , 2009, DOI: 10.1371/journal.pgen.1000605
Abstract: Dynamic regulation of chromatin structure is of fundamental importance for modulating genomic activities in higher eukaryotes. The opposing activities of Polycomb group (PcG) and trithorax group (trxG) proteins are part of a chromatin-based cellular memory system ensuring the correct expression of specific transcriptional programs at defined developmental stages. The default silencing activity of PcG proteins is counteracted by trxG proteins that activate PcG target genes and prevent PcG mediated silencing activities. Therefore, the timely expression and regulation of PcG proteins and counteracting trxG proteins is likely to be of fundamental importance for establishing cell identity. Here, we report that the chromodomain/helicase/DNA–binding domain CHD3 proteins PICKLE (PKL) and PICKLE RELATED2 (PKR2) have trxG-like functions in plants and are required for the expression of many genes that are repressed by PcG proteins. The pkl mutant could partly suppress the leaf and flower phenotype of the PcG mutant curly leaf, supporting the idea that CHD3 proteins and PcG proteins antagonistically determine cell identity in plants. The direct targets of PKL in roots include the PcG genes SWINGER and EMBRYONIC FLOWER2 that encode subunits of Polycomb repressive complexes responsible for trimethylating histone H3 at lysine 27 (H3K27me3). Similar to mutants lacking PcG proteins, lack of PKL and PKR2 caused reduced H3K27me3 levels and, therefore, increased expression of a set of PcG protein target genes in roots. Thus, PKL and PKR2 are directly required for activation of PcG protein target genes and in roots are also indirectly required for repression of PcG protein target genes. Reduced PcG protein activity can lead to cell de-differentiation and callus-like tissue formation in pkl pkr2 mutants. Thus, in contrast to mammals, where PcG proteins are required to maintain pluripotency and to prevent cell differentiation, in plants PcG proteins are required to promote cell differentiation by suppressing embryonic development.
The Gag Cleavage Product, p12, is a Functional Constituent of the Murine Leukemia Virus Pre-Integration Complex
Adi Prizan-Ravid equal contributor,Efrat Elis equal contributor,Nihay Laham-Karam,Sara Selig,Marcelo Ehrlich,Eran Bacharach
PLOS Pathogens , 2010, DOI: 10.1371/journal.ppat.1001183
Abstract: The p12 protein is a cleavage product of the Gag precursor of the murine leukemia virus (MLV). Specific mutations in p12 have been described that affect early stages of infection, rendering the virus replication-defective. Such mutants showed normal generation of genomic DNA but no formation of circular forms, which are markers of nuclear entry by the viral DNA. This suggested that p12 may function in early stages of infection but the precise mechanism of p12 action is not known. To address the function and follow the intracellular localization of the wt p12 protein, we generated tagged p12 proteins in the context of a replication-competent virus, which allowed for the detection of p12 at early stages of infection by immunofluorescence. p12 was found to be distributed to discrete puncta, indicative of macromolecular complexes. These complexes were localized to the cytoplasm early after infection, and thereafter accumulated adjacent to mitotic chromosomes. This chromosomal accumulation was impaired for p12 proteins with a mutation that rendered the virus integration-defective. Immunofluorescence demonstrated that intracellular p12 complexes co-localized with capsid, a known constituent of the MLV pre-integration complex (PIC), and immunofluorescence combined with fluorescent in situ hybridization (FISH) revealed co-localization of the p12 proteins with the incoming reverse transcribed viral DNA. Interactions of p12 with the capsid and with the viral DNA were also demonstrated by co-immunoprecipitation. These results imply that p12 proteins are components of the MLV PIC. Furthermore, a large excess of wt PICs did not rescue the defect in integration of PICs derived from mutant p12 particles, demonstrating that p12 exerts its function as part of this complex. Altogether, these results imply that p12 proteins are constituent of the MLV PIC and function in directing the PIC from the cytoplasm towards integration.
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