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PubMed | Hannover Medical School, University of Montréal, Genomic Expression, University of Duisburg - Essen and 2 more.
Type: Journal Article | Journal: Leukemia | Year: 2016

Genetic and epigenetic aberrations contribute to the initiation and progression of acute myeloid leukemia (AML). GFI1, a zinc-finger transcriptional repressor, exerts its function by recruiting histone deacetylases to target genes. We present data that low expression of GFI1 is associated with an inferior prognosis of AML patients. To elucidate the mechanism behind this, we generated a humanized mouse strain with reduced GFI1 expression (GFI1-KD). Here we show that AML development induced by onco-fusion proteins such as MLL-AF9 or NUP98-HOXD13 is accelerated in mice with low human GFI1 expression. Leukemic cells from animals that express low levels of GFI1 show increased H3K9 acetylation compared to leukemic cells from mice with normal human GFI1 expression, resulting in the upregulation of genes involved in leukemogenesis. We investigated a new epigenetic therapy approach for this subgroup of AML patients. We could show that AML blasts from GFI1-KD mice and from AML patients with low GFI1 levels were more sensitive to treatment with histone acetyltransferase inhibitors than cells with normal GFI1 expression levels. We suggest therefore that GFI1 has a dose-dependent role in AML progression and development. GFI1 levels are involved in epigenetic regulation, which could open new therapeutic approaches for AML patients.

Woo S.,Fred Hutchinson Cancer Research Center | Zhang X.,Fred Hutchinson Cancer Research Center | Sauteraud R.,Fred Hutchinson Cancer Research Center | Robert F.,Genomic Expression | And 2 more authors.
Bioinformatics | Year: 2013

MNase-Seq and ChIP-Seq have evolved as popular techniques to study chromatin and histone modification. Although many tools have been developed to identify enriched regions, software tools for nucleosome positioning are still limited. We introduce a flexible and powerful open-source R package, PING 2.0, for nucleosome positioning using MNase-Seq data or MNase- or sonicated- ChIP-Seq data combined with either single-end or paired-end sequencing. PING uses a model-based approach, which enables nucleosome predictions even in the presence of low read counts. We illustrate PING using two paired-end datasets from Saccharomyces cerevisiae and compare its performance with nucleR and ChIPseqR.Availability: PING 2.0 is available from the Bioconductor website at It can run on Linux, Mac and Windows.Contact: Supplementary Information: Supplementary material is available at Bioinformatics online. © 2013 The Author 2013. Published by Oxford University Press.

Goldbeck R.,University of Campinas | Ramos M.M.,University of Campinas | Pereira G.A.G.,Genomic Expression | Maugeri-Filho F.,University of Campinas
Bioresource Technology | Year: 2013

The objective of the present study was to evaluate the production of cellulolytic enzymes by Acremonium strictum isolated from Brazilian Biome using different substrates. Fermentations were initially carried out using commercial substrates, including microcrystalline cellulose (AVICEL® and SERVACEL®) and carboxymethylcellulose (CMC). This was followed by fermentations performed using lignocellulosic biomass: sugarcane bagasse pretreated at different intensities. The fermentations were carried out in shakers at 150. rpm, 30 °C for 240. h. Four enzyme activities were determined: CMCase, FPase, cellobiase and β-glucosidase. Among the substrates used, results showed that the sugarcane bagasse submitted to mild pretreatment was that which induced the microorganism to produce greater cellulolytic activities. This substrate was employed in the optimization study of cellulase production by A. strictum. © 2012 Elsevier Ltd.

Martinez-Juarez A.,National Institute of Perinatology | Uribe-Figueroa L.,Genomic Expression | Quintana-Palma M.,National Institute of Perinatology | Razo-Aguilera G.,National Institute of Perinatology | Sevilla-Montoya R.,National Institute of Perinatology
Cytogenetic and Genome Research | Year: 2014

Pure partial trisomy 2p patients have rarely been reported. Oligonucleotide array analysis has proved to be important for examining 2p rearrangements to delineate the involved segment and to rule out additional imbalances modifying the phenotype. Here, we report 2 siblings with an unbalanced translocation that led to a partial trisomy 2p (p22.3pter) and a terminal deletion of 12q (q24.33qter). This finding was characterized by the molecular karyotyping of both siblings. The 12q loss spanned approximately 300 kb and did not yield clinical features in our patients. The trisomic region in the short arm of chromosome 2 spanned 32.8 Mb and yielded phenotypic features of pure distal 2p trisomy, notably facial anomalies, growth failure, and psychomotor delay. The clinical features of our patients help to delineate the phenotype of the pure trisomy 2p syndrome. Patient 2 also showed a horseshoe kidney which is a previously unrecognized defect associated with this syndrome. © 2014 S. Karger AG, Basel.

Agency: European Commission | Branch: H2020 | Program: SME-1 | Phase: PHC-12-2014-1 | Award Amount: 71.43K | Year: 2015

The BLACANDI project aims to dramatically improve the diagnosis and management of bladder cancer patients by substituting a highly invasive and expensive test with a non-invasive and inexpensive test. Bladder cancer is the 6th most common cancer with an estimated 357,000 new cases worldwide every year, of which 180,000 are European. This type of cancer has the highest lifetime treatment costs per patient (pp) of all cancers. This high incidence, coupled with its relapsing nature, means that bladder cancer poses an enormous burden on health care systems. Current diagnostics and recurrence routine tests are performed through highly invasive and expensive procedures, such as cystoscopy. The Danish SME Genomic Expression Aps has licensed a technology composed of a patented filtration device that enhances the selection of tumor cells in urine, and aims at the clinical validation of a new combination of biomarkers. Our solution BLACANDI (Filtration Device in combination with selected biomarkers) is currently being tested in a small clinical trial in Denmark, in patients presenting with hematuria (blood in urine). Preliminary results indicate that the test can substitute cystoscopy identifying more than 90% of all bladder cancer patients. Substituting routine cystoscopy with the BLACANDI system could cut the cost of diagnosis and managing bladder cancer in half. In Europe the cost of diagnosing bladder cancer is 1.8 billion/year, thus we could save 900 million. Whereas the technology behind the filtration device and the selected biomarkers is already demonstrated, further maturation of the tests into fully commercial and operational solutions is hampered by the absence of a large clinical validation of the BLACANDI system. Furthermore, there is a need to corroborate our business strategy, since it requires customization to different health care systems. This phase 1 feasibility study provides us that opportunity.

The invention provides a process for synthesizing genes and other long double stranded polynucleotides by assembling very short oligonucleotides into partly double stranded polynucleotides, and then connecting these partly double stranded polynucleotide subassemblies with linkers comprised of very short oligonucleotides. In one embodiment, the correct order of the polynucleotide subassemblies is coded in overhangs present at each end of the partly double stranded polynucleotide subassemblies. Linkers having a sequence complimentary to the combined overhangs connect adjacent subassemblies, which are then ligated together. In one preferred embodiment the oligos are six bases long, for which there are only 4096 different possible sequence permutations. A complete library of oligos of this size and scale can be cost-effectively synthesized and quality controlled, avoiding the typical errors and yield issues associated with phosphoramidite synthesis of longer oligos. Furthermore, the limited oligo library size supports development of a laboratory-scale gene synthesis machine.

Kulcheski F.R.,Federal University of Rio Grande do Sul | de Oliveira L.F.V.,Federal University of Rio Grande do Sul | Molina L.G.,Federal University of Rio Grande do Sul | Almerao M.P.,Federal University of Rio Grande do Sul | And 12 more authors.
BMC Genomics | Year: 2011

Background: Small RNAs (19-24 nt) are key regulators of gene expression that guide both transcriptional and post-transcriptional silencing mechanisms in eukaryotes. Current studies have demonstrated that microRNAs (miRNAs) act in several plant pathways associated with tissue proliferation, differentiation, and development and in response to abiotic and biotic stresses. In order to identify new miRNAs in soybean and to verify those that are possibly water deficit and rust-stress regulated, eight libraries of small RNAs were constructed and submitted to Solexa sequencing.Results: The libraries were developed from drought-sensitive and tolerant seedlings and rust-susceptible and resistant soybeans with or without stressors. Sequencing the library and subsequent analyses detected 256 miRNAs. From this total, we identified 24 families of novel miRNAs that had not been reported before, six families of conserved miRNAs that exist in other plants species, and 22 families previously reported in soybean. We also observed the presence of several isomiRNAs during our analyses. To validate novel miRNAs, we performed RT-qPCR across the eight different libraries. Among the 11 miRNAs analyzed, all showed different expression profiles during biotic and abiotic stresses to soybean. The majority of miRNAs were up-regulated during water deficit stress in the sensitive plants. However, for the tolerant genotype, most of the miRNAs were down regulated. The pattern of miRNAs expression was also different for the distinct genotypes submitted to the pathogen stress. Most miRNAs were down regulated during the fungus infection in the susceptible genotype; however, in the resistant genotype, most miRNAs did not vary during rust attack. A prediction of the putative targets was carried out for conserved and novel miRNAs families.Conclusions: Validation of our results with quantitative RT-qPCR revealed that Solexa sequencing is a powerful tool for miRNA discovery. The identification of differentially expressed plant miRNAs provides molecular evidence for the possible involvement of miRNAs in the process of water deficit- and rust-stress responses. © 2011 Kulcheski et al; licensee BioMed Central Ltd.

PubMed | Genomic Expression and Laval University
Type: Journal Article | Journal: Eukaryotic cell | Year: 2015

Proper modulation of promoter chromatin architecture is crucial for gene regulation in order to precisely and efficiently orchestrate various cellular activities. Previous studies have identified the stimulatory effect of the histone-modifying complex NuA4 on the incorporation of the histone variant H2A.Z (Htz1) at the PHO5 promoter (A. Auger, L. Galarneau, M. Altaf, A. Nourani, Y. Doyon, R. T. Utley, D. Cronier, S. Allard, and J. Ct, Mol Cell Biol 28:2257-2270, 2008, In vitro studies with a reconstituted system also indicated an intriguing cross talk between NuA4 and the H2A.Z-loading complex, SWR-C (M. Altaf, A. Auger, J. Monnet-Saksouk, J. Brodeur, S. Piquet, M. Cramet, N. Bouchard, N. Lacoste, R. T. Utley, L. Gaudreau, J. Ct, J Biol Chem 285:15966-15977, 2010, In this work, we investigated the role of the NuA4 scaffold subunit Eaf1 in global gene expression and genome-wide incorporation of Htz1. We found that loss of Eaf1 affects Htz1 levels mostly at the promoters that are normally highly enriched in the histone variant. Analysis of eaf1 mutant cells by expression array unveiled a relationship between NuA4 and the gene network implicated in the purine biosynthesis pathway, as EAF1 deletion cripples induction of several ADE genes. NuA4 directly interacts with Bas1 activation domain, a key transcription factor of adenine genes. Chromatin immunoprecipitation (ChIP) experiments demonstrate that nucleosomes on the inactive ADE17 promoter are acetylated already by NuA4 and enriched in Htz1. Upon derepression, these poised nucleosomes respond rapidly to activate ADE gene expression in a mechanism likely reminiscent of the PHO5 promoter, leading to nucleosome disassembly. These detailed molecular events depict a specific case of cross talk between NuA4-dependent acetylation and incorporation of histone variant Htz1, presetting the chromatin structure over ADE promoters for subsequent chromatin remodeling and activated transcription.

PubMed | U.S. Environmental Protection Agency, NSF International and Genomic Expression
Type: Journal Article | Journal: Toxicological sciences : an official journal of the Society of Toxicology | Year: 2016

Use of archival resources has been limited to date by inconsistent methods for genomic profiling of degraded RNA from formalin-fixed paraffin-embedded (FFPE) samples. RNA-sequencing offers a promising way to address this problem. Here, we evaluated transcriptomic dose responses using RNA-sequencing in paired FFPE and frozen (FROZ) samples from 2 archival studies in mice, one<2 years old and the other>20 years old. Experimental treatments included 3 different doses of di(2-ethylhexyl)phthalate or dichloroacetic acid for the recently archived and older studies, respectively. Total RNA was ribo-depleted and sequenced using the Illumina HiSeq platform. In the recently archived study, FFPE samples had 35% lower total counts compared to FROZ samples but high concordance in fold-change values of differentially expressed genes (DEGs) (r

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