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PubMed2005

SuperSAGE combined with PCR walking allows global gene expression profiling of banana (Musa acuminata), a non-model organism.

Super-serial analysis of gene expression (SuperSAGE) was used to characterize, for the first time, the global gene expression pattern in banana (Musa acuminata). A total of 10,196 tags were generated from leaf tissue, representing 5,292 expressed genes. Forty-nine tags of the top 100 most abundantly expressed transcripts were annotated by homology to cDNA or EST sequences. Typically for leaf tissue, analysis of the transcript profiles showed that the majority of the abundant transcripts are involved in energy production, mainly photosynthesis. However, the most abundant tag was derived from a type 3 metallothionein transcript, which accounted for nearly 3% of total transcripts analysed. Furthermore, the 26-bp long SuperSAGE tags were applied in 3'-rapid amplification of cDNA ends (3'RACE) for the identification of unknown tags. In combination with thermal asymmetric interlaced PCR (TAIL-PCR), this allowed the recovery of a full gene sequence of a novel NADPH:protochlorophyllide oxidoreductase, the key enzyme in chlorophyll biosynthesis. SuperSAGE in conjunction with 3'RACE and TAIL-PCR will be a powerful tool for transcriptomics of non-model, but otherwise important organisms.

Base Sequence↗

PubMed2006

Analysis of cell migration using whole-genome expression profiling of migratory cells in the Drosophila ovary.

Cell migration contributes to normal development and homeostasis as well as to pathological processes such as inflammation and tumor metastasis. Previous genetic screens have revealed signaling pathways that govern follicle cell migrations in the Drosophila ovary, but few downstream targets of the critical transcriptional regulators have been identified. To characterize the gene expression profile of two migratory cell populations and identify Slbo targets, we purified border cells and centripetal cells expressing the mouse CD8 antigen and carried out whole-genome microarray analysis. Genes predicted to control actin dynamics and the endocytic and secretory pathways were overrepresented in the migratory cell transcriptome. Mutations in five genes, including ttk, failed to complement previously isolated mutations that cause cell migration defects in mosaic clones. Functional analysis revealed a role for the Notch-activating protease Kuzbanian in border cell migration and identified Tie as a guidance receptor for the border cells.

Animals↗

PubMed2004

Transcriptional signature of flavopiridol-induced tumor cell death.

Flavopiridol has been shown to inhibit the proliferation of a variety of human tumor cells and is currently undergoing clinical evaluation in cancer treatment. Although the antiproliferative effect of flavopiridol has been attributed to the inhibition of cyclin-dependent kinases 2 and 4, recent reports indicate that the mechanism responsible for the cell death induced by this agent is more complex. To provide insight into the molecular processes mediating flavopiridol-induced cytotoxicity and to investigate the availability of markers indicative of its activity, we have applied cDNA microarray technology. Gene expression profiles were determined for four human tumor cell lines (prostate carcinomas PC3 and DU145 and gliomas SF359 and U251) following exposure to selected concentrations of flavopiridol. Treatment of these cell lines with a concentration of flavopiridol sufficient to reduce survival to 10% resulted in the identification of a set of 209 genes, the expression of which were altered in each of the cell lines. This common set of 209 gene expression changes suggested that flavopiridol-induced cell death can be defined in terms of a specific transcriptome. The flavopiridol death transcriptome consisted primarily of down-regulated genes; however, there were also a significant number of genes with increased expression. Whereas causal relationships were not established, these data suggest molecular events/processes that may be associated with flavopiridol-induced tumor cell death. Moreover, the identification of a set of gene expression changes in four human tumor cell lines suggests that such a transcriptome may be applicable to investigations of flavopiridol pharmacodynamics.

Antineoplastic Agents↗

PubMed2002

The propagator (retarded Green function) formalism as a new calculation method to predict the time evolution of bands in capillary electrophoresis and microchannels.

Capillary electrophoresis (CE) and microchannel (MC) techniques are important tools in chemical and biological sciences, mainly in the study of genomes, transcriptomes, proteomes, metabolomes, and organic as well as inorganic ions. The speed of DNA sequencing increased significantly during the last decade with the use of capillary electrophoresis (CE). The time evolution of the bands' spatial profile inside capillaries and channels is of paramount importance, since the main goal of these techniques is to maximize resolution (the ratio between the spacing of the peaks and their mean standard deviations). In the present work, the propagator (retarded Green function) formalism is applied to solve a few problems which are typical for CE and MC. We also apply this mathematical method to the problem of velocity gradients along the capillary, i.e., the time evolution of the bands is analyzed when they enter regions where they migrate with different velocities.

Diffusion↗

PubMed2004

Proteomics of the Drosophila immune response.

Completion of the Drosophila genome has enabled the use of proteomic approaches for studying complex processes such as the innate immune defense against microorganisms. Microbial infection leads to the activation of responses involving changes at translational and post-translational levels. Proteomics is a tool for assessing such changes in protein expression, localization and post-translational modification. Recently, several studies have reported whole-genome analyses of the Drosophila immune response, both at the transcriptome and proteome levels, leading to a more comprehensive view of fly immunity. In this review, we describe and compare the proteomic techniques used in these analyses and discuss the results obtained by differential protein profiling of the Drosophila immune response.

Animals↗

PubMed2026

Immune cell-specific genetic architecture of Alzheimer's disease revealed by multi-omics analysis for therapeutic target discovery and prioritization.

Alzheimer's disease (AD) is a multifactorial neurodegenerative condition in which accumulating genetic and molecular evidence implicates dysregulation of peripheral immune processes in disease pathogenesis. Nevertheless, the contribution of distinct peripheral immune cell subsets and associated gene regulatory landscapes to AD risk remains incompletely defined. To address this gap, we integrated single-cell expression quantitative trait loci (sc‑eQTL) data from the OneK1K cohort with AD GWAS summary statistics. We systematically interrogated immune cell-specific genes for their contributions to AD risk by integrating genetic causal inference with Bayesian colocalization analyses, and identified 24 eGenes that passed both the MR significance threshold (P < 0.05) and the criterion for strong shared genetic signals (PP.H4 > 0.8). Notable candidates included GATS, HLA-DOB, HLA-DQA1, PM20D1, and others, with each gene demonstrating a cell-type-specific association restricted to its corresponding immune cell type, such as monocytes, CD8 + T cells, or B cells. Independent peripheral blood single-cell transcriptomic data further supported disease-associated shifts in cell-type-specific expression patterns in AD. Phenome-wide association studies (PheWAS) indicated limited associations with off-target traits, indicating a favorable safety profile for therapeutic intervention, with the exceptions of B4GALNT3, PM20D1, and CNN2. Integration of immune gene targets with pharmacological databases yielded three candidate compound, including NSC321521 (targeting HLA-DQA1), phenoxybenzamine (targeting GSTP1), and rimexolone (targeting BIN1). Among these compounds, Predicted blood-brain barrier permeability was observed only for phenoxybenzamine and rimexolone, with docking studies indicating stable interactions, such as those between NSC321521 and HLA-DQA1, phenoxybenzamine and GSTP1, and rimexolone and BIN1. This integrative approach highlights key immune‑cell‑specific genes involved in AD and proposes repurposable drugs with central nervous system potential, paving the way for more targeted immunomodulatory strategies in AD.

Humans↗

PubMed2005

Analysis of methylation-sensitive transcriptome identifies GADD45a as a frequently methylated gene in breast cancer.

Treatment of the breast cancer cell line, MDAMB468 with the DNA methylation inhibitor, 5-azacytidine (5-AzaC) results in growth arrest, whereas the growth of the normal breast epithelial line DU99 (telomerase immortalized) is relatively unaffected. Comparing gene expression profiles of these two lines after 5-AzaC treatment, we identified 36 genes that had relatively low basal levels in MDAMB468 cells compared to the DU99 line and were induced in the cancer cell line but not in the normal breast epithelial line. Of these genes, 33 have associated CpG islands greater than 300 bp in length but only three have been previously described as targets for aberrant methylation in human cancer. Northern blotting for five of these genes (alpha-Catenin, DTR, FYN, GADD45a, and Zyxin) verified the array results. Further analysis of one of these genes, GADD45a, showed that 5-AzaC induced expression in five additional breast cancer cell lines with little or no induction in three additional lines derived from normal breast epithelial cells. The CpG island associated with GADD45a was analysed by bisulfite sequencing, sampling over 100 CpG dinucleotides. We found that four CpG's, located approximately 700 bp upstream of the transcriptional start site are methylated in the majority of breast cancer cell lines and primary tumors but not in DNA from normal breast epithelia or matched lymphocytes from cancer patients. Therefore, this simple method of dynamic transcriptional profiling yielded a series of novel methylation-sensitive genes in breast cancer including the BRCA1 and p53 responsive gene, GADD45a.

Azacitidine↗

PubMed2025

Contribution of the Brain-Gut-Microbiome Axis to Intergenerational Abnormalities in a Rat Model of Perioperative Neurocognitive Disorder.

BACKGROUND: The brain-gut-microbiome (BGM) axis is a communication network through which the brain and gastrointestinal microbiota interact via neural, hormonal, immune, and gene expression mechanisms. Gut microbiota dysbiosis is thought to contribute to neurocognitive disorders, including perioperative neurocognitive disorder, and to various metabolic abnormalities. Recently, the authors reported that sevoflurane induces neurocognitive deficits in exposed rats as well as their future offspring, with male offspring being particularly affected (intergenerational perioperative neurocognitive disorder). In this study, the authors examined in the same animals whether the intergenerational effects of sevoflurane involve abnormalities in the BGM axis, and whether they are mitigated by paternal pretreatment with either the Na + -K + -Cl - (NKCC1) Cl - transporter inhibitor bumetanide or the glucocorticoid receptor inhibitor RU486, as previously demonstrated for neurocognitive deficits. METHODS: Male Sprague-Dawley rats (F0 generation) were exposed to 2.1% sevoflurane for 3 h on postnatal days 56, 58, and 60 (F0M_S group). Before each sevoflurane exposure, distinct experimental groups of F0 males received bumetanide (F0M_BS group) or RU486 (F0M_RS group). These males were mated on postnatal day 90 to produce offspring (F1 generation). Gut microbiota were profiled using 16S rRNA gene sequencing, and brain changes analyzed via RNA sequencing of hippocampal samples. RESULTS: F1 male offspring of F0M_S sires exhibited heightened corticosterone responses to stress, increased inflammatory markers, altered hippocampal transcriptomes, gut microbiota dysbiosis, elevated serum low-density lipoprotein cholesterol levels, and increased body weight. The only abnormality observed in F1 females was a shift in microbial diversity. F0M_S displayed profound alterations in hippocampal transcriptome, while microbial diversity was the only parameter affected in their gut microbiota. Bumetanide or RU486 mitigated most abnormalities, except increased body weight in F1 males. CONCLUSIONS: Paternal sevoflurane exposure in rats induces BGM axis abnormalities, particularly in male offspring, despite the absence of direct anesthetic exposure. Pretreatment with bumetanide or RU486 showed therapeutic efficacy.

Animals↗

PubMed2003

Quantitative assessment of transcriptome differences between brain territories.

Transcriptome analysis of mammalian brain structures is a potentially powerful approach in addressing the diversity of cerebral functions. Here, we used a microassay for serial analysis of gene expression (SAGE) to generate quantitative mRNA expression profiles of normal adult mouse striatum, nucleus accumbens, and somatosensory cortex. Comparison of these profiles revealed 135 transcripts heterogeneously distributed in the brain. Among them, a majority (78), although matching a registered sequence, are novel regional markers. To improve the anatomical resolution of our analysis, we performed in situ hybridization and observed unique expression patterns in discrete brain regions for a number of candidates. We assessed the distribution of the new markers in peripheral tissues using quantitative RT-PCR, Northern hybridization, and published SAGE data. In most cases, expression was higher in the brain than in peripheral tissues. Because the markers were selected according to their expression level, without reference to prior knowledge, our studies provide an unbiased, comprehensive molecular signature for various mammalian brain structures that can be used to investigate their plasticity under a variety of circumstances.

Animals↗

PubMed2005

Antisense transcription in the mammalian transcriptome.

Antisense transcription (transcription from the opposite strand to a protein-coding or sense strand) has been ascribed roles in gene regulation involving degradation of the corresponding sense transcripts (RNA interference), as well as gene silencing at the chromatin level. Global transcriptome analysis provides evidence that a large proportion of the genome can produce transcripts from both strands, and that antisense transcripts commonly link neighboring "genes" in complex loci into chains of linked transcriptional units. Expression profiling reveals frequent concordant regulation of sense/antisense pairs. We present experimental evidence that perturbation of an antisense RNA can alter the expression of sense messenger RNAs, suggesting that antisense transcription contributes to control of transcriptional outputs in mammals.

Animals↗

PubMed2006

Global transcriptome analysis of the responses of a fluoroquinolone-resistant Streptococcus pneumoniae mutant and its parent to ciprofloxacin.

Streptococcus pneumoniae M22 is a multidrug-resistant mutant selected after exposure of capsulated wild-type S. pneumoniae NCTC 7465 (strain M4) to ciprofloxacin. DNA microarray analysis comparing the gene expression profiles of strain M22 with those of strain M4 showed that strain M22 constitutively expressed 22 genes at levels higher than those observed in strain M4 under all conditions studied. These included the genes encoding the enzymes involved in branched-chain amino acid biosynthesis and two genes (patA and patB) with sequences suggestive of ABC transporter proteins. Expression of the patA and patB genes was induced by ciprofloxacin in both strains, but in strain M4 it only reached the levels observed in strain M22 after long incubation with high concentrations of ciprofloxacin. The altered expression profile observed with strain M22 suggested that the mutation or mutations acquired during resistance selection bring the cell into a state in which the expression of critical genes is preemptively altered to correct for the potential effects of ciprofloxacin on gene expression in the parent strain.

Ciprofloxacin↗

PubMed2006

Genome-wide analysis of mRNAs regulated by Drosha and Argonaute proteins in Drosophila melanogaster.

RNA silencing pathways are conserved gene regulation mechanisms that elicit decay and/or translational repression of mRNAs complementary to short interfering RNAs and microRNAs (miRNAs). The fraction of the transcriptome regulated by these pathways is not known, but it is thought that each miRNA may have hundreds of targets. To identify transcripts regulated by silencing pathways at the genomic level, we examined mRNA expression profiles in Drosophila melanogaster cells depleted of four Argonaute paralogs (i.e., AGO1, AGO2, PIWI, or Aubergine) that play essential roles in RNA silencing. We also profiled cells depleted of the miRNA-processing enzyme Drosha. The results reveal that transcripts differentially expressed in Drosha-depleted cells have highly correlated expression in the AGO1 knockdown and are significantly enriched in predicted and validated miRNA targets. The levels of a subset of miRNA targets are also regulated by AGO2. Moreover, AGO1 and AGO2 silence the expression of a common set of mobile genetic elements. Together, these results indicate that the functional overlap between AGO1 and AGO2 in Drosophila is more important than previously thought.

Animals↗

PubMed2005

A transcriptome map of cellular transformation by the fos oncogene.

BACKGROUND: The c-fos gene was originally identified as the cellular homolog of the oncogene v-fos carried by the Finkel-Biskis-Jenkins and Finkel-Biskis-Reilly murine osteogenic sarcoma retroviruses. Sustained expression of fos is sufficient to induce cellular transformation in vitro and tumorigenesis in vivo. Fos functions as a component of the AP-1 transcription factor complex to regulate gene transcription and several differentially expressed genes have been identified in cells transformed by fos. We have extended these studies by constructing a cellular system for conditional transformation by v-fos. Using Affymetrix-based DNA microarray technology, we analyzed transcriptional changes over the course of transformation and reversion in an inducible v-fos system. RESULTS: Microarray analyses of temporal gene expression during the process of v-fos mediated cellular transformation and morphological reversion revealed a remarkably dynamic transcriptome. Of the more than 8000 genes analyzed in this study, 3766 genes were categorized into 18 gene-expression patterns by using self-organizing map analysis. By combining the analysis of gene expression profiles in stably transformed cells with the analysis of sequential expression patterns during conditional transformation, we identified a relatively small cohort of genes implicated in v-fos mediated cellular transformation. CONCLUSION: This approach defines a general conditional cell transformation system that can be used to study the endogenous transcription regulatory mechanisms involved in transformation and tumorigenesis. In addition, this study is the first reported analysis of dynamic changes in gene expression throughout experimentally controlled morphological transformation mediated by v-fos.

Cell Line↗

PubMed2005

In vitro expansion of human mesenchymal stem cells: choice of serum is a determinant of cell proliferation, differentiation, gene expression, and transcriptome stability.

Human bone marrow mesenchymal stem cells (hMSCs) represent an appealing source of adult stem cells for cell therapy and tissue engineering, as they are easily obtained and expanded while maintaining their multilineage differentiation potential. All current protocols for in vitro culture of hMSCs include fetal bovine serum (FBS) as nutritional supplement. FBS is an undesirable additive to cells that are expanded for therapeutic purposes in humans because the use of FBS carries the risk of transmitting viral and prion diseases and proteins that may initiate xenogeneic immune responses. In the present study, we have therefore investigated if autologous serum (AS) or allogeneic human serum (alloHS) could replace FBS for the expansion of hMSCs in vitro. We discovered that the choice of serum affected hMSCs at several different levels. First, hMSCs in AS proliferated markedly faster than hMSCs in FBS, whereas use of alloHS resulted in hMSC growth arrest and death. Second, hMSCs in FBS differentiated more rapidly toward mesenchymal lineages compared with hMSCs in AS. Interestingly, genome-wide microarray analysis identified several transcripts involved in cell cycle and differentiation that were differentially regulated between hMSCs in FBS and AS. Finally, several transcripts, including some involved in cell cycle inhibition, were upregulated in hMSCs in FBS at a late passage, whereas the hMSC transcriptome in AS was remarkably stable. Thus, hMSCs may be expanded rapidly and with stable gene expression in AS in the absence of growth factors, whereas FBS induces a more differentiated and less stable transcriptional profile.

Animals↗

PubMed2006

Comparative transcriptional profiling of the lung reveals shared and distinct features of Streptococcus pneumoniae and influenza A virus infection.

Pneumonia is the most common cause of death from infectious disease in the western hemisphere. Pathophysiological and protective processes are initiated by pattern recognition of microbial structures. To provide the molecular framework for a better understanding of processes relevant to host defence in pneumonia, we performed pulmonary transcriptome analysis in mice infected with the major bacterial and viral agents of community-acquired pneumonia, Streptococcus pneumoniae and influenza A virus. We detected differential expression of 1300 genes after infection with either pathogen. Of these, approximately 36% or 30% were specific for pneumococcal or influenza infection, respectively, yielding pathogen-specific as well as shared inflammatory transcriptional signatures. These results not only reveal a differential response on the cytokine and chemokine levels but also emphasize the important role of genes implicated in regulation and fine tuning of inflammation. As one, albeit unexpected, key feature of pneumococcal pneumonia we discovered down-regulation of B-cell responses, probably reflecting a pneumococcal virulence strategy. The pathophysiological consequences of influenza A virus infection were reflected by the emerging protective T-cell response and differential induction of genes involved in tissue regeneration and proliferation. These data provide new insights into pathogenesis of the most common forms of pneumonia, highlighting the value of transcriptional profiling for the elucidation of underlying mechanisms.

Animals↗

PubMed2006

Global gene expression profiling of dimethylnitrosamine-induced liver fibrosis: from pathological and biochemical data to microarray analysis.

The development of hepatocellular carcinoma (HCC) is generally preceded by cirrhosis, which occurs at the end stage of fibrosis. This is a common and potentially lethal problem of chronic liver disease in Asia. The development of microarrays permits us to monitor transcriptomes on a genome-wide scale; this has dramatically speeded up a comprehensive understanding of the disease process. Here we used dimethylnitrosamine (DMN), a nongenotoxic hepatotoxin, to induce rat necroinflammatory and hepatic fibrosis. During the 6-week time course, histopathological, biochemical, and quantitative RT-PCR analyses confirmed the incidence of necroinflammatory and hepatic fibrosis in this established rat model system. Using the Affymetrix microarray chip, 256 differentially expressed genes were identified from the liver injury samples. Hierarchical clustering of gene expression using a gene ontology database allowed the identification of several stage-specific characters and functionally related clusters that encode proteins related to metabolism, cell growth/maintenance, and response to external challenge. Among these genes, we classified 44 potential necroinflammatory-related genes and 62 potential fibrosis-related markers or drug targets based on histopathological scores. We also compared the results with other data on well-known markers and various other microarray datasets that are available. In conclusion, we believe that the molecular picture of necroinflammatory and hepatic fibrosis from this study may provide novel biological insights into the development of early liver damage molecular classifiers than can be used for basic research and in clinical applications. A public accessible website is available at http://LiverFibrosis.nchc.org.tw:8080/LF.

Animals↗

PubMed2005

A fully Bayesian model to cluster gene-expression profiles.

MOTIVATION: With cDNA or oligonucleotide chips, gene-expression levels of essentially all genes in a genome can be simultaneously monitored over a time-course or under different experimental conditions. After proper normalization of the data, genes are often classified into co-expressed classes (clusters) to identify subgroups of genes that share common regulatory elements, a common function or a common cellular origin. With most methods, e.g. k-means, the number of clusters needs to be specified in advance; results depend strongly on this choice. Even with likelihood-based methods, estimation of this number is difficult. Furthermore, missing values often cause problems and lead to the loss of data. RESULTS: We propose a fully probabilistic Bayesian model to cluster gene-expression profiles. The number of classes does not need to be specified in advance; instead it is adjusted dynamically using a Reversible Jump Markov Chain Monte Carlo sampler. Imputation of missing values is integrated into the model. With simulations, we determined the speed of convergence of the sampler as well as the accuracy of the inferred variables. Results were compared with the widely used k-means algorithm. With our method, biologically related co-expressed genes could be identified in a yeast transcriptome dataset, even when some values were missing. AVAILABILITY: The code is available at http://genome.tugraz.at/BayesianClustering/

Algorithms↗

PubMed2006

Evaluation of gene expression analysis using RNA-targeted partial genome arrays.

Highly parallel cDNA targeting microarrays have been established over the last years as the quasi-standard for genome wide expression profiling in pro- and eukaryotes. Protocols for the direct detection of RNA or aRNA (amplified RNA) are currently emerging. This allows to circumvent the bias introduced by enzymatic target molecule preparation. To systematically evaluate the extent of non-specific target binding on oligonucleotide microarrays designed for total RNA expression profiling, a model system of 70-mer probes targeting genes involved in magnetosome formation (mam genes) of the bacterium Magnetospirillum gryphiswaldense was established utilizing wild-type strain MSR-1 and an isogenic deletion mutant MSR-1B that lacks all mam genes. An optimized protocol for the direct chemical labelling of total cellular RNAs was used. A linear correlation between the amount of applied RNA and the mean global background intensity was found which enables a simple and unbiased way of normalizing the data. The results obtained with the mam deletion mutant MSR-1B revealed a significant number of false positive signals, even under optimal hybridization conditions. This indicates a high degree of non-specific binding in microarray experiments when using longer oligo- or polynucleotides and RNA as target molecule. Comparative microarray analysis of an MSR-1B culture and two MSR-1 wild-type cultures grown under different conditions was done via a three-colour hybridization assay. The additional information provided by the MSR-1B transcriptome revealed differential gene expression in the two MSR-1 cultures, which was otherwise undetectable.

Gene Expression Profiling↗