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Permutation-validated principal components analysis of microarray data
Jobst Landgrebe, Wolfgang Wurst, Gerhard Welzl
Genome Biology , 2002, DOI: 10.1186/gb-2002-3-4-research0019
Abstract: We used PCA to detect the major sources of variance underlying the hybridization conditions followed by gene selection based on PCA-derived and permutation-based test statistics. We validated our method by applying it to well characterized yeast cell-cycle data and to two datasets from our laboratory. We could describe the major sources of variance, select informative genes and visualize the relationship of genes and arrays. We observed differences in the level of the explained variance and the interpretability of the selected genes.Combining data visualization and permutation-based gene selection, permutation-validated PCA enables one to illustrate gene-expression variance between several conditions and to select genes by taking into account the relationship of between-group to within-group variance of genes. The method can be used to extract the leading sources of variance from microarray data, to visualize relationships between genes and hybridizations and to select informative genes in a statistically reliable manner. This selection accounts for the level of reproducibility of replicates or group structure as well as gene-specific scatter. Visualization of the data can support a straightforward biological interpretation.Microarrays have become standard tools for gene expression analysis as the messenger RNA levels of thousands of genes can be measured in one assay. In a standard microarray experiment, total RNA or mRNA is extracted from cells or tissue, labeled by reverse transcription with radioactive or fluorescent-tag-labeled nucleotides and hybridized to the arrays. After hybridization and washing, the arrays are scanned and the hybridization intensities at each spot are determined by image-analysis software. Two-channel microarrays open up the possibility of carrying out many hybridizations in parallel using a common reference RNA. In such experiments, different experimental conditions can be compared to each other. In many cases, different conditions are a
Bioinformatics Identification of Modules of Transcription Factor Binding Sites in Alzheimer's Disease-Related Genes by In Silico Promoter Analysis and Microarrays
Regina Augustin,Stefan F. Lichtenthaler,Michael Greeff,Jens Hansen,Wolfgang Wurst,Dietrich Trümbach
International Journal of Alzheimer's Disease , 2011, DOI: 10.4061/2011/154325
Abstract: The molecular mechanisms and genetic risk factors underlying Alzheimer's disease (AD) pathogenesis are only partly understood. To identify new factors, which may contribute to AD, different approaches are taken including proteomics, genetics, and functional genomics. Here, we used a bioinformatics approach and found that distinct AD-related genes share modules of transcription factor binding sites, suggesting a transcriptional coregulation. To detect additional coregulated genes, which may potentially contribute to AD, we established a new bioinformatics workflow with known multivariate methods like support vector machines, biclustering, and predicted transcription factor binding site modules by using in silico analysis and over 400 expression arrays from human and mouse. Two significant modules are composed of three transcription factor families: CTCF, SP1F, and EGRF/ZBPF, which are conserved between human and mouse APP promoter sequences. The specific combination of in silico promoter and multivariate analysis can identify regulation mechanisms of genes involved in multifactorial diseases. 1. Introduction Alzheimer’s disease (AD) is the most common form of dementia, which slowly destroys neurons and causes serious cognitive disability [1]. Characteristics of AD are insoluble amyloid plaques and neurofibrillary tangles in the brains of AD patients, which extend progressively to neocortical brain areas during AD [2]. AD exists in a sporadic and familial (heritable) form. Mutations in amyloid-beta precursor protein (APP), presenilin1, and presenilin2 are associated with early-onset forms of familial AD, whereas sporadic AD occurs in people over the age of 65 years [3]. APP was the first gene linked to AD and is located on chromosome 21. APP is cleaved by different proteases named α-, β-, and γ-secretase. These proteases control the generation of the amyloid-β peptide (Aβ), which is considered the culprit in AD. β- and γ-secretase cleavage leads to Aβ formation. β-secretase is the aspartyl protease BACE1 [4, 5]. A homolog of BACE1, BACE2, cleaves within the Aβ domain and does not contribute to Aβ generation. γ-secretase is a heterotetramer consisting of the four subunits presenilin 1 or 2 (PS1, PS2), Aph1, Nicastrin, and Pen-2 [6]. Aggregates of Aβ are neurotoxic and start the so-called amyloid cascade, which describes the molecular mechanisms leading to AD, including formation of plaques and tangles [1]. The third protease, the alpha-secretase ADAM10 [7, 8], avoids formation of Aβ, because it cleaves APP inside the Aβ sequence [9]. Additionally,
Pro-Survival Role for Parkinson's Associated Gene DJ-1 Revealed in Trophically Impaired Dopaminergic Neurons
Liviu Aron,Pontus Klein,Thu-Trang Pham,Edgar R. Kramer,Wolfgang Wurst,Rüdiger Klein
PLOS Biology , 2012, DOI: 10.1371/journal.pbio.1000349
Abstract: The mechanisms underlying the selective death of substantia nigra (SN) neurons in Parkinson disease (PD) remain elusive. While inactivation of DJ-1, an oxidative stress suppressor, causes PD, animal models lacking DJ-1 show no overt dopaminergic (DA) neuron degeneration in the SN. Here, we show that aging mice lacking DJ-1 and the GDNF-receptor Ret in the DA system display an accelerated loss of SN cell bodies, but not axons, compared to mice that only lack Ret signaling. The survival requirement for DJ-1 is specific for the GIRK2-positive subpopulation in the SN which projects exclusively to the striatum and is more vulnerable in PD. Using Drosophila genetics, we show that constitutively active Ret and associated Ras/ERK, but not PI3K/Akt, signaling components interact genetically with DJ-1. Double loss-of-function experiments indicate that DJ-1 interacts with ERK signaling to control eye and wing development. Our study uncovers a conserved interaction between DJ-1 and Ret-mediated signaling and a novel cell survival role for DJ-1 in the mouse. A better understanding of the molecular connections between trophic signaling, cellular stress and aging could uncover new targets for drug development in PD.
Spatial Analysis of Expression Patterns Predicts Genetic Interactions at the Mid-Hindbrain Boundary
Dominik M. Wittmann,Florian Bl?chl,Dietrich Trümbach,Wolfgang Wurst,Nilima Prakash,Fabian J. Theis
PLOS Computational Biology , 2009, DOI: 10.1371/journal.pcbi.1000569
Abstract: The isthmic organizer mediating differentiation of mid- and hindbrain during vertebrate development is characterized by a well-defined pattern of locally restricted gene expression domains around the mid-hindbrain boundary (MHB). This pattern is established and maintained by a regulatory network between several transcription and secreted factors that is not yet understood in full detail. In this contribution we show that a Boolean analysis of the characteristic spatial gene expression patterns at the murine MHB reveals key regulatory interactions in this network. Our analysis employs techniques from computational logic for the minimization of Boolean functions. This approach allows us to predict also the interplay of the various regulatory interactions. In particular, we predict a maintaining, rather than inducing, effect of Fgf8 on Wnt1 expression, an issue that remained unclear from published data. Using mouse anterior neural plate/tube explant cultures, we provide experimental evidence that Fgf8 in fact only maintains but does not induce ectopic Wnt1 expression in these explants. In combination with previously validated interactions, this finding allows for the construction of a regulatory network between key transcription and secreted factors at the MHB. Analyses of Boolean, differential equation and reaction-diffusion models of this network confirm that it is indeed able to explain the stable maintenance of the MHB as well as time-courses of expression patterns both under wild-type and various knock-out conditions. In conclusion, we demonstrate that similar to temporal also spatial expression patterns can be used to gain information about the structure of regulatory networks. We show, in particular, that the spatial gene expression patterns around the MHB help us to understand the maintenance of this boundary on a systems level.
Differential gene expression in ADAM10 and mutant ADAM10 transgenic mice
Claudia Prinzen, Dietrich Trümbach, Wolfgang Wurst, Kristina Endres, Rolf Postina, Falk Fahrenholz
BMC Genomics , 2009, DOI: 10.1186/1471-2164-10-66
Abstract: To assess the influence of ADAM10 on the gene expression profile in the brain, we performed a microarray analysis using RNA isolated from brains of five months old mice overexpressing either the α-secretase ADAM10, or a dominant-negative mutant (dn) of this enzyme. As compared to non-transgenic wild-type mice, in ADAM10 transgenic mice 355 genes, and in dnADAM10 mice 143 genes were found to be differentially expressed. A higher number of genes was differentially regulated in double-transgenic mouse strains additionally expressing the human APP[V717I] mutant.Overexpression of proteolytically active ADAM10 affected several physiological pathways, such as cell communication, nervous system development, neuron projection as well as synaptic transmission. Although ADAM10 has been implicated in Notch and β-catenin signaling, no significant changes in the respective target genes were observed in adult ADAM10 transgenic mice.Real-time RT-PCR confirmed a downregulation of genes coding for the inflammation-associated proteins S100a8 and S100a9 induced by moderate ADAM10 overexpression. Overexpression of the dominant-negative form dnADAM10 led to a significant increase in the expression of the fatty acid-binding protein Fabp7, which also has been found in higher amounts in brains of Down syndrome patients.In general, there was only a moderate alteration of gene expression in ADAM10 overexpressing mice. Genes coding for pro-inflammatory or pro-apoptotic proteins were not over-represented among differentially regulated genes. Even a decrease of inflammation markers was observed. These results are further supportive for the strategy to treat AD by increasing the α-secretase activity.Accumulation of amyloid β-peptides (Aβ) in the brain is believed to contribute to the development of Alzheimer disease (AD). Soluble oligomeric forms of Aβ are neurotoxic [1-3]. Aβ, a 40–43 amino acid-comprising proteolytical fragment of the amyloid precursor protein (APP), is released from APP by seq
Voluntary wheel running in mice increases the rate of neurogenesis without affecting anxiety-related behaviour in single tests
Lillian Garrett, D Chichung Lie, Martin Hrabé de Angelis, Wolfgang Wurst, Sabine M H?lter
BMC Neuroscience , 2012, DOI: 10.1186/1471-2202-13-61
Abstract: Running altered measures of locomotion and exploration, but not anxiety-related behaviour in either test. 14?days running significantly increased proliferation, and differentiation and survival were increased after both running durations. 28?day running mice also exhibited an increased rate of maturation. Furthermore, there was a significant positive correlation between the amount of proliferation, but not maturation, and anxiety measures in the open field of the 28?day running mice.Overall, this evidence suggests that without repeated testing, newly born mature neurons may not be involved in the genesis of anxiety per se.
Pro-Survival Role for Parkinson's Associated Gene DJ-1 Revealed in Trophically Impaired Dopaminergic Neurons
Liviu Aron,Pontus Klein,Thu-Trang Pham,Edgar R. Kramer,Wolfgang Wurst,Rüdiger Klein
PLOS Biology , 2010, DOI: 10.1371/journal.pbio.1000349
Abstract: The mechanisms underlying the selective death of substantia nigra (SN) neurons in Parkinson disease (PD) remain elusive. While inactivation of DJ-1, an oxidative stress suppressor, causes PD, animal models lacking DJ-1 show no overt dopaminergic (DA) neuron degeneration in the SN. Here, we show that aging mice lacking DJ-1 and the GDNF-receptor Ret in the DA system display an accelerated loss of SN cell bodies, but not axons, compared to mice that only lack Ret signaling. The survival requirement for DJ-1 is specific for the GIRK2-positive subpopulation in the SN which projects exclusively to the striatum and is more vulnerable in PD. Using Drosophila genetics, we show that constitutively active Ret and associated Ras/ERK, but not PI3K/Akt, signaling components interact genetically with DJ-1. Double loss-of-function experiments indicate that DJ-1 interacts with ERK signaling to control eye and wing development. Our study uncovers a conserved interaction between DJ-1 and Ret-mediated signaling and a novel cell survival role for DJ-1 in the mouse. A better understanding of the molecular connections between trophic signaling, cellular stress and aging could uncover new targets for drug development in PD.
Plant-mediated links between detritivores and aboveground herbivores
Susanne Wurst*
Frontiers in Plant Science , 2013, DOI: 10.3389/fpls.2013.00380
Abstract: Most studies on plant-mediated above–belowground interactions focus on soil biota with direct trophic links to plant roots such as root herbivores, pathogens, and symbionts. Detritivorous soil fauna, though ubiquitous and present in high abundances and biomasses in soil, are under-represented in those studies. Understanding of their impact on plants is mainly restricted to growth and nutrient uptake parameters. Detritivores have been shown to affect secondary metabolites and defense gene expression in aboveground parts of plants, with potential impacts on aboveground plant–herbivore interactions. The proposed mechanisms range from nutrient mobilization effects and impacts on soil microorganisms to defense induction by passive or active ingestion of roots. Since their negative effects (disruption or direct feeding of roots) may be counterbalanced by their overall beneficial effects (nutrient mobilization), detritivores may not harm, but rather enable plants to respond to aboveground herbivore attacks in a more efficient way. Both more mechanistic and holistic approaches are needed to better understand the involvement of detritivores in plant-mediated above–belowground interactions and their potential for sustainable agriculture.
Computational identification and experimental validation of microRNAs binding to the Alzheimer-related gene ADAM10
Regina Augustin, Kristina Endres, Sven Reinhardt, Peer-Hendrik Kuhn, Stefan F Lichtenthaler, Jens Hansen, Wolfgang Wurst, Dietrich Trümbach
BMC Medical Genetics , 2012, DOI: 10.1186/1471-2350-13-35
Abstract: MiRNA binding sites in the human ADAM10 3' untranslated region were predicted using the RNA22, RNAhybrid and miRanda programs and ranked by specific selection criteria with respect to AD such as differential regulation in AD patients and tissue-specific expression. Furthermore, target genes of miR-103, miR-107 and miR-1306 were derived from six publicly available miRNA target site prediction databases. Only target genes predicted in at least four out of six databases in the case of miR-103 and miR-107 were compared to genes listed in the AlzGene database including genes possibly involved in AD. In addition, the target genes were used for Gene Ontology analysis and literature mining. Finally, we used a luciferase assay to verify the potential effect of these three miRNAs on ADAM10 3'UTR in SH-SY5Y cells.Eleven miRNAs were selected, which have evolutionary conserved binding sites. Three of them (miR-103, miR-107, miR-1306) were further analysed as they are linked to AD and most strictly conserved between different species. Predicted target genes of miR-103 (p-value = 0.0065) and miR-107 (p-value = 0.0009) showed significant overlap with the AlzGene database except for miR-1306. Interactions between miR-103 and miR-107 to genes were revealed playing a role in processes leading to AD. ADAM10 expression in the reporter assay was reduced by miR-1306 (28%), miR-103 (45%) and miR-107 (52%).Our approach shows the requirement of incorporating specific, disease-associated selection criteria into the prediction process to reduce the amount of false positive predictions. In summary, our method identified three miRNAs strongly suggested to be involved in AD, which possibly regulate ADAM10 expression and hence offer possibilities for the development of therapeutic treatments of AD.
A powerful transgenic tool for fate mapping and functional analysis of newly generated neurons
Jingzhong Zhang, Florian Giesert, Karina Kloos, Daniela M Vogt Weisenhorn, Ludwig Aigner, Wolfgang Wurst, Sebastien Couillard-Despres
BMC Neuroscience , 2010, DOI: 10.1186/1471-2202-11-158
Abstract: In the DCX-CreERT2 transgenic mice, expression of CreERT2 was restricted to DCX+ cells. In the CNS of transgenic embryos and adult DCX-CreERT2 mice, tamoxifen administration caused the transient translocation of CreERT2 to the nucleus, allowing for the recombination of loxP-flanked sequences. In our system, tamoxifen administration at E14.5 resulted in reporter gene activation throughout the developing CNS of transgenic embryos. In the adult CNS, neurogenic regions were the primary sites of tamoxifen-induced reporter gene activation. In addition, reporter expression could also be detected outside of neurogenic regions in cells physiologically expressing DCX (e.g. piriform cortex, corpus callosum, hypothalamus). Four weeks after recombination, the vast majority of reporter-expressing cells were found to co-express NeuN, revealing the neuronal fate of DCX+ cells upon maturation.This first validation demonstrates that our new DCX-CreERT2 transgenic mouse model constitutes a powerful tool to investigate neurogenesis, migration and their long-term fate of neuronal precursors. Moreover, it allows for a targeted activation or deletion of specific genes in neuronal precursors and will thereby contribute to unravel the molecular mechanisms controlling neurogenesis.Neurogenesis is a strictly controlled process generating and maintaining the complex CNS cytoarchitecture. In the adult brain, neurogenesis constitutes in addition a form of cellular neuronal plasticity by continuously generating new neurons from resident neural stem cells (NSCs). Neurogenesis progresses through several sequential events, including proliferation, neuronal lineage restriction of precursors, cell cycle exit, migration and integration into target area, differentiation, as well as morphological and functional maturation. At the end of this process, newly generated cells can be found as functionally integrated and active neurons [1-3].Neuronal precursors and newly generated neurons can be identified by
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