TY  - JOUR
A1  - Aukema, Sietse M.
A1  - Kreuz, Markus
A1  - Kohler, Christian W.
A1  - Rosolowski, Maciej
A1  - Hasenclever, Dirk
A1  - Hummel, Michael
A1  - Küppers, Ralf
A1  - Lenze, Diddo
A1  - Ott, German
A1  - Pott, Christiane
A1  - Richter, Julia
A1  - Rosenwald, Andreas
A1  - Szczepanowski, Monika
A1  - Schwaenen, Carsten
A1  - Stein, Harald
A1  - Trautmann, Heiko
A1  - Wessendorf, Swen
A1  - Trümper, Lorenz
A1  - Loeffler, Markus
A1  - Spang, Rainer
A1  - Kluin, Philip M.
A1  - Klapper, Wolfram
A1  - Siebert, Reiner
T1  - Biological characterization of adult MYC-translocation-positive mature B-cell lymphomas other than molecular Burkitt lymphoma
JF  - Haematologica
N2  - Chromosomal translocations affecting the MYC oncogene are the biological hallmark of Burkitt lymphomas but also occur in a subset of other mature B-cell lymphomas. If accompanied by a chromosomal break targeting the BCL2 and/or BCL6 oncogene these MYC translocation-positive (MYC+) lymphomas are called double-hit lymphomas, otherwise the term single-hit lymphomas is applied. In order to characterize the biological features of these MYC+ lymphomas other than Burkitt lymphoma we explored, after exclusion of molecular Burkitt lymphoma as defined by gene expression profiling, the molecular, pathological and clinical aspects of 80 MYC-translocation-positive lymphomas (31 single-hit, 46 double-hit and 3 MYC+-lymphomas with unknown BCL6 status). Comparison of single-hit and double-hit lymphomas revealed no difference in MYC partner (IG/non-IG), genomic complexity, MYC expression or gene expression profile. Double-hit lymphomas more frequently showed a germinal center B-cell-like gene expression profile and had higher IGH and MYC mutation frequencies. Gene expression profiling revealed 130 differentially expressed genes between BCL6(+)/MYC+ and BCL2(+)/MYC+ double-hit lymphomas. BCL2(+)/MYC+ double-hit lymphomas more frequently showed a germinal center B-like gene expression profile. Analysis of all lymphomas according to MYC partner (IG/non-IG) revealed no substantial differences. In this series of lymphomas, in which immunochemotherapy was administered in only a minority of cases, single-hit and double-hit lymphomas had a similar poor outcome in contrast to the outcome of molecular Burkitt lymphoma and lymphomas without the MYC break. Our data suggest that, after excluding molecular Burkitt lymphoma and pediatric cases, MYC+ lymphomas are biologically quite homogeneous with single-hit and double-hit lymphomas as well as IG-MYC and non-IG-MYC+ lymphomas sharing various molecular characteristics.
KW  - Rituximab plus
KW  - cyclophsophamide
KW  - c-myc
KW  - gene expression
KW  - genomic aberrations
KW  - follicular lymphoma
KW  - prognostic factor
KW  - poor prognosis
KW  - grade 3B
KW  - distinct
Y1  - 2014
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-116882
SN  - 1592-8721
VL  - 99
IS  - 4
ER  - 
TY  - JOUR
A1  - Garcia, Tzintzuni I.
A1  - Matos, Isa
A1  - Shen, Yingjia
A1  - Pabuwal, Vagmita
A1  - Coelho, Maria Manuela
A1  - Wakamatsu, Yuko
A1  - Schartl, Manfred
A1  - Walter, Ronald B.
T1  - Novel Method for Analysis of Allele Specific Expression in Triploid Oryzias latipes Reveals Consistent Pattern of Allele Exclusion
JF  - PLOS ONE
N2  - Assessing allele-specific gene expression (ASE) on a large scale continues to be a technically challenging problem. Certain biological phenomena, such as X chromosome inactivation and parental imprinting, affect ASE most drastically by completely shutting down the expression of a whole set of alleles. Other more subtle effects on ASE are likely to be much more complex and dependent on the genetic environment and are perhaps more important to understand since they may be responsible for a significant amount of biological diversity. Tools to assess ASE in a diploid biological system are becoming more reliable. Non-diploid systems are, however, not uncommon. In humans full or partial polyploid states are regularly found in both healthy (meiotic cells, polynucleated cell types) and diseased tissues (trisomies, non-disjunction events, cancerous tissues). In this work we have studied ASE in the medaka fish model system. We have developed a method for determining ASE in polyploid organisms from RNAseq data and we have implemented this method in a software tool set. As a biological model system we have used nuclear transplantation to experimentally produce artificial triploid medaka composed of three different haplomes. We measured ASE in RNA isolated from the livers of two adult, triploid medaka fish that showed a high degree of similarity. The majority of genes examined (82%) shared expression more or less evenly among the three alleles in both triploids. The rest of the genes (18%) displayed a wide range of ASE levels. Interestingly the majority of genes (78%) displayed generally consistent ASE levels in both triploid individuals. A large contingent of these genes had the same allele entirely suppressed in both triploids. When viewed in a chromosomal context, it is revealed that these genes are from large sections of 4 chromosomes and may be indicative of some broad scale suppression of gene expression.
KW  - RNA-SEQ data
KW  - copy-number alteration
KW  - squalius alburnoides
KW  - gene expression
KW  - medaka
KW  - variant detection
KW  - transplantation
KW  - genome
KW  - generation
KW  - evolution
Y1  - 2014
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-116000
SN  - 1932-6203
VL  - 9
IS  - 6
ER  - 
TY  - JOUR
A1  - Hyun, Tae Kyung
A1  - van der Graaff, Eric
A1  - Albacete, Alfonso
A1  - Eom, Seung Hee
A1  - Grosskinsky, Dominik K.
A1  - Böhm, Hannah
A1  - Janschek, Ursula
A1  - Rim, Yeonggil
A1  - Ali, Walid Wahid
A1  - Kim, Soo Young
A1  - Roitsch, Thomas
T1  - The Arabidopsis PLAT Domain Protein1 is Critically Involved in Abiotic Stress Tolerance
JF  - PLOS ONE
N2  - Despite the completion of the Arabidopsis genome sequence, for only a relatively low percentage of the encoded proteins experimental evidence concerning their function is available. Plant proteins that harbour a single PLAT (Polycystin, Lipoxygenase, Alpha-toxin and Triacylglycerol lipase) domain and belong to the PLAT-plant-stress protein family are ubiquitously present in monocot and dicots. However, the function of PLAT-plant-stress proteins is still poorly understood. Therefore, we have assessed the function of the uncharacterised Arabidopsis PLAT-plant-stress family members through a combination of functional genetic and physiological approaches. PLAT1 overexpression conferred increased abiotic stress tolerance, including cold, drought and salt stress, while loss-of-function resulted in opposite effects on abiotic stress tolerance. Strikingly, PLAT1 promoted growth under non-stressed conditions. Abiotic stress treatments induced PLAT1 expression and caused expansion of its expression domain. The ABF/ABRE transcription factors, which are positive mediators of abscisic acid signalling, activate PLAT1 promoter activity in transactivation assays and directly bind to the ABRE elements located in this promoter in electrophoretic mobility shift assays. This suggests that PLAT1 represents a novel downstream target of the abscisic acid signalling pathway. Thus, we showed that PLAT1 critically functions as positive regulator of abiotic stress tolerance, but also is involved in regulating plant growth, and thereby assigned a function to this previously uncharacterised PLAT domain protein. The functional data obtained for PLAT1 support that PLAT-plant-stress proteins in general could be promising targets for improving abiotic stress tolerance without yield penalty.
KW  - salicylic acid
KW  - gene expression
KW  - signal transduction
KW  - cold stress
KW  - salt stress
KW  - abscisic acid
KW  - endoplasmatic reticulum
KW  - transcription factors
KW  - pseudomonas syringae
KW  - plants response
Y1  - 2014
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-114648
VL  - 9
IS  - 11
ER  - 
TY  - JOUR
A1  - Morton, Charles Oliver
A1  - Fliesser, Mirjam
A1  - Dittrich, Marcus
A1  - Müller, Tobias
A1  - Bauer, Ruth
A1  - Kneitz, Susanne
A1  - Hope, William
A1  - Rogers, Thomas Richard
A1  - Einsele, Hermann
A1  - Löffler, Jürgen
T1  - Gene Expression Profiles of Human Dendritic Cells Interacting with Aspergillus fumigatus in a Bilayer Model of the Alveolar Epithelium/Endothelium Interface
N2  - The initial stages of the interaction between the host and Aspergillus fumigatus at the alveolar surface of the human lung are critical in the establishment of aspergillosis. Using an in vitro bilayer model of the alveolus, including both the epithelium (human lung adenocarcinoma epithelial cell line, A549) and endothelium (human pulmonary artery epithelial cells, HPAEC) on transwell membranes, it was possible to closely replicate the in vivo conditions. Two distinct sub-groups of dendritic cells (DC), monocyte-derived DC (moDC) and myeloid DC (mDC), were included in the model to examine immune responses to fungal infection at the alveolar surface. RNA in high quantity and quality was extracted from the cell layers on the transwell membrane to allow gene expression analysis using tailored custom-made microarrays, containing probes for 117 immune-relevant genes. This microarray data indicated minimal induction of immune gene expression in A549 alveolar epithelial cells in response to germ tubes of A. fumigatus. In contrast, the addition of DC to the system greatly increased the number of differentially expressed immune genes. moDC exhibited increased expression of genes including CLEC7A, CD209 and CCL18 in the absence of A. fumigatus compared to mDC. In the presence of A. fumigatus, both DC subgroups exhibited up-regulation of genes identified in previous studies as being associated with the exposure of DC to A. fumigatus and exhibiting chemotactic properties for neutrophils, including CXCL2, CXCL5, CCL20, and IL1B. This model closely approximated the human alveolus allowing for an analysis of the host pathogen interface that complements existing animal models of IA.
KW  - aspergillus fumigatus
KW  - gene expression
KW  - immune receptors
KW  - immune response
KW  - denritic cells
KW  - B cell receptors
KW  - gene regulation
KW  - RNA extraction
Y1  - 2014
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-112893
ER  - 
TY  - JOUR
A1  - Naseem, Muhammad
A1  - Kunz, Meik
A1  - Dandekar, Thomas
T1  - Probing the unknowns in cytokinin-mediated immune defense in Arabidopsis with systems biology approaches
JF  - Bioinformatics and Biology Insights
N2  - Plant hormones involving salicylic acid (SA), jasmonic acid (JA), ethylene (Et), and auxin, gibberellins, and abscisic acid (ABA) are known to regulate host immune responses. However, plant hormone cytokinin has the potential to modulate defense signaling including SA and JA. It promotes plant pathogen and herbivore resistance; underlying mechanisms are still unknown. Using systems biology approaches, we unravel hub points of immune interaction mediated by cytokinin signaling in Arabidopsis. High-confidence Arabidopsis protein-protein interactions (PPI) are coupled to changes in cytokinin-mediated gene expression. Nodes of the cellular interactome that are enriched in immune functions also reconstitute sub-networks. Topological analyses and their specific immunological relevance lead to the identification of functional hubs in cellular interactome. We discuss our identified immune hubs in light of an emerging model of cytokinin-mediated immune defense against pathogen infection in plants.
KW  - plant hormones
KW  - systems biology
KW  - interaction networks
KW  - gene expression
KW  - cytokinin
Y1  - 2014
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-120199
SN  - 1177-9322
VL  - 8
ER  - 
TY  - JOUR
A1  - Nguyen, Tu N.
A1  - Müller, Laura S. M.
A1  - Park, Sung Hee
A1  - Siegel, T. Nicolai
A1  - Günzl, Arthur
T1  - Promoter occupancy of the basal class I transcription factor A differs strongly between active and silent VSG expression sites in Trypanosoma brucei
JF  - Nucleic Acid Research
N2  - Monoallelic expression within a gene family is found in pathogens exhibiting antigenic variation and in mammalian olfactory neurons. Trypanosoma brucei, a lethal parasite living in the human bloodstream, expresses variant surface glycoprotein (VSG) from 1 of 15 bloodstream expression sites (BESs) by virtue of a multifunctional RNA polymerase I. The active BES is transcribed in an extranucleolar compartment termed the expression site body (ESB), whereas silent BESs, located elsewhere within the nucleus, are repressed epigenetically. The regulatory mechanisms, however, are poorly understood. Here we show that two essential subunits of the basal class I transcription factor A (CITFA) predominantly occupied the promoter of the active BES relative to that of a silent BES, a phenotype that was maintained after switching BESs in situ. In these experiments, high promoter occupancy of CITFA was coupled to high levels of both promoter-proximal RNA abundance and RNA polymerase I occupancy. Accordingly, fluorescently tagged CITFA-7 was concentrated in the nucleolus and the ESB. Because a ChIP-seq analysis found that along the entire BES, CITFA-7 is specifically enriched only at the promoter, our data strongly indicate that monoallelic BES transcription is activated by a mechanism that functions at the level of transcription initiation.
KW  - RNA-polymerase-I
KW  - blood-stream forms
KW  - acrican trypanosomes
KW  - gene expression
KW  - antigenic variation
KW  - ribosomal RNA
KW  - plasmodium falciparum
KW  - virulence genes
KW  - subunit
KW  - complex
Y1  - 2014
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-117232
SN  - 1362-4962
VL  - 42
IS  - 5
ER  - 
TY  - JOUR
A1  - Pascoalino, Bruno
A1  - Dindar, Gülcin
A1  - Vieira-da-Rocha, João P.
A1  - Machado, Carlos Renato
A1  - Janzen, Christian J.
A1  - Schenkman, Sergio
T1  - Characterization of two different Asf1 histone chaperones with distinct cellular localizations and functions in Trypanosoma brucei
JF  - Nucleic Acids Research
N2  - The anti-silencing function protein 1 (Asf1) is a chaperone that forms a complex with histones H3 and H4 facilitating dimer deposition and removal from chromatin. Most eukaryotes possess two different Asf1 chaperones but their specific functions are still unknown. Trypanosomes, a group of early-diverged eukaryotes, also have two, but more divergent Asf1 paralogs than Asf1 of higher eukaryotes. To unravel possible different functions, we characterized the two Asf1 proteins in Trypanosoma brucei. Asf1A is mainly localized in the cytosol but translocates to the nucleus in S phase. In contrast, Asf1B is predominantly localized in the nucleus, as described for other organisms. Cytosolic Asf1 knockdown results in accumulation of cells in early S phase of the cell cycle, whereas nuclear Asf1 knockdown arrests cells in S/G2 phase. Overexpression of cytosolic Asf1 increases the levels of histone H3 and H4 acetylation. In contrast to cytosolic Asf1, overexpression of nuclear Asf1 causes less pronounced growth defects in parasites exposed to genotoxic agents, prompting a function in chromatin remodeling in response to DNA damage. Only the cytosolic Asf1 interacts with recombinant H3/H4 dimers in vitro. These findings denote the early appearance in evolution of distinguishable functions for the two Asf1 chaperons in trypanosomes.
KW  - chromatin assembly factors
KW  - DNA-damage checkpoint
KW  - tousled-like kinases
KW  - saccharomyes cerevisiae
KW  - gene expression
KW  - acetyltransferase RTT109
KW  - african trypanosomes
KW  - antigenetic variation
KW  - cycle regulation
KW  - nuclear import
Y1  - 2014
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-117220
SN  - 1362-4962
VL  - 42
IS  - 5
ER  - 
TY  - JOUR
A1  - Reynolds, David
A1  - Cliffe, Laura
A1  - Förstner, Konrad U.
A1  - Hon, Chung-Chau
A1  - Siegel, T. Nicolai
A1  - Sabatini, Robert
T1  - Regulation of transcription termination by glucosylated hydroxymethyluracil, base J, in Leishmania major and Trypanosoma brucei
JF  - Nucleic Acids Research
N2  - Base J, beta-d-glucosyl-hydroxymethyluracil, is an epigenetic modification of thymine in the nuclear DNA of flagellated protozoa of the order Kinetoplastida. J is enriched at sites involved in RNA polymerase ( RNAP) II initiation and termination. Reduction of J in Leishmania tarentolae via growth in BrdU resulted in cell death and indicated a role of J in the regulation of RNAP II termination. To further explore J function in RNAP II termination among kinetoplastids and avoid indirect effects associated with BrdU toxicity and genetic deletions, we inhibited J synthesis in Leishmania major and Trypanosoma brucei using DMOG. Reduction of J in L. major resulted in genome-wide defects in transcription termination at the end of polycistronic gene clusters and the generation of antisense RNAs, without cell death. In contrast, loss of J in T. brucei did not lead to genome-wide termination defects; however, the loss of J at specific sites within polycistronic gene clusters led to altered transcription termination and increased expression of downstream genes. Thus, J regulation of RNAP II transcription termination genome-wide is restricted to Leishmania spp., while in T. brucei it regulates termination and gene expression at specific sites within polycistronic gene clusters.
KW  - RNA-polymerase-II
KW  - variant surface glycoprotein
KW  - SWI2/SNF2-like protein
KW  - messenger RNA
KW  - polycistronic transcription
KW  - DNA glycosation
KW  - hela cells
KW  - gene expression
KW  - genome
KW  - 5-bromodeoxyuridine
Y1  - 2014
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-117863
VL  - 42
IS  - 15
ER  - 
TY  - JOUR
A1  - Sander, Brigitta
A1  - de Jong, Daphne
A1  - Rosenwald, Andreas
A1  - Xie, Wanling
A1  - Balagué, Olga
A1  - Calaminici, Maria
A1  - Carreras, Joaquim
A1  - Gaulard, Philippe
A1  - Gribben, John
A1  - Hagenbeek, Anton
A1  - Kersten, Marie José
A1  - Molina, Thierry Jo
A1  - Lee, Abigail
A1  - Montes-Moreno, Santiago
A1  - Ott, German
A1  - Raemaekers, John
A1  - Salles, Gilles
A1  - Sehn, Laurie
A1  - Thorns, Christoph
A1  - Wahlin, Bjorn E.
A1  - Gascoyne, Randy D.
A1  - Weller, Edie
T1  - The reliability of immunohistochemical analysis of the tumor microenvironment in follicular lymphoma: a validation study from the Lunenburg Lymphoma Biomarker Consortium
JF  - Haematologica
N2  - The cellular microenvironment in follicular lymphoma is of biological and clinical importance. Studies on the clinical significance of non-malignant cell populations have generated conflicting results, which may partly be influenced by poor reproducibility in immunohistochemical marker quantification. In this study, the reproducibility of manual scoring and automated microscopy based on a tissue microarray of 25 follicular lymphomas as compared to flow cytometry is evaluated. The agreement between manual scoring and flow cytometry was moderate for CD3, low for CD4, and moderate to high for CD8, with some laboratories scoring closer to the flow cytometry results. Agreement in manual quantification across the 7 laboratories was low to moderate for CD3, CD4, CD8 and FOXP3 frequencies, moderate for CD21, low for MIB1 and CD68, and high for CD10. Manual scoring of the architectural distribution resulted in moderate agreement for CD3, CD4 and CD8, and low agreement for FOXP3 and CD68. Comparing manual scoring to automated microscopy demonstrated that manual scoring increased the variability in the low and high frequency interval with some laboratories showing a better agreement with automated scores. Manual scoring reliably identified rare architectural patterns of T-cell infiltrates. Automated microscopy analyses for T-cell markers by two different instruments were highly reproducible and provided acceptable agreement with flow cytometry. These validation results provide explanations for the heterogeneous findings on the prognostic value of the microenvironment in follicular lymphoma. We recommend a more objective measurement, such as computer-assisted scoring, in future studies of the prognostic impact of microenvironment in follicular lymphoma patients.
KW  - CD/metabolism
KW  - flow cytometry
KW  - antigens
KW  - regulatory T-cells
KW  - independent predictor
KW  - gene expression
KW  - high numbers
KW  - CD40 ligand
KW  - Riutximab
KW  - survival
KW  - marcophages
KW  - transformation
KW  - in-vitro
Y1  - 2014
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-116875
SN  - 1592-8721
VL  - 99
IS  - 4
ER  - 
TY  - JOUR
A1  - Sanz-Moreno, Adrian
A1  - Fuhrmann, David
A1  - Wolf, Elmar
A1  - von Eyss, Björn
A1  - Eilers, Martin
A1  - Elsässer, Hans-Peter
T1  - Miz1 Deficiency in the Mammary Gland Causes a Lactation Defect by Attenuated Stat5 Expression and Phosphorylation
JF  - PLOS ONE
N2  - Miz1 is a zinc finger transcription factor with an N-terminal POZ domain. Complexes with Myc, Bcl-6 or Gfi-1 repress expression of genes like Cdkn2b (p15(Ink4)) or Cd-kn1a (p21(Cip1)). The role of Miz1 in normal mammary gland development has not been addressed so far. Conditional knockout of the Miz1 POZ domain in luminal cells during pregnancy caused a lactation defect with a transient reduction of glandular tissue, reduced proliferation and attenuated differentiation. This was recapitulated in vitro using mouse mammary gland derived HC11 cells. Further analysis revealed decreased Stat5 activity in Miz1 Delta POZ mammary glands and an attenuated expression of Stat5 targets. Gene expression of the Prolactin receptor (PrlR) and ErbB4, both critical for Stat5 phosphorylation (pStat5) or pStat5 nuclear translocation, was decreased in Miz1 Delta POZ females. Microarray, ChIP-Seq and gene set enrichment analysis revealed a down-regulation of Miz1 target genes being involved in vesicular transport processes. Our data suggest that deranged intracellular transport and localization of PrlR and ErbB4 disrupt the Stat5 signalling pathway in mutant glands and cause the observed lactation phenotype.
KW  - C-MYC
KW  - transcription factor MIZ-1
KW  - breast-cancer cells
KW  - gene expression
KW  - epithelial cells
KW  - prolactin
KW  - transgenic mice
KW  - growth
KW  - differentiation
KW  - proliferation
Y1  - 2014
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-117286
VL  - 9
IS  - 2
ER  -