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PubMed2004

Global analysis of gene expression in mammalian kidney.

The past decade has seen the achievement of sequencing of human, rat and mouse genomes and the development of high-throughput methods for quantitative monitoring of gene expression. The aim of the beginning post-genomic era is to determine the function of all these genes, a challenge in which the community of physiologists should have a leading role. In this short review, we discuss the relevance, feasibility and impact of transcriptome analysis in renal physiology. Comparison of transcriptomes demonstrates that cell lines are poor physiological models, making it necessary to work on native kidney tissue. Palliating kidney heterogeneity therefore requires the development of methods for transcriptome analysis sensitive enough to be compatible with microdissected nephron segments. Axial comparison of transcriptomes along the human nephron unexpectedly points out that the segmentation of nephrons concerns not only genes involved in solute and water transport functions and their regulation, but also genes related to the control of cell division, differentiation and apoptosis. Comparison of transcriptome of a same nephron segment from mice under different pathophysiological conditions outlines the wide pleiotropy of kidney function regulations. Both types of comparative studies also identify yet unknown transcripts specifically expressed along the nephron or under pathophysiological conditions.

Animals↗

PubMed2006

Review: on the analysis and interpretation of correlations in metabolomic data.

A remarkable inherent feature of cellular metabolism is that the concentrations of a small but significant number of metabolites are strongly correlated when measurements of biological replicates are performed. This review seeks to summarize the recent efforts to elucidate the origin of these observed correlations and points out several aspects concerning their interpretation. It is argued that correlations between metabolites differ profoundly from their transcriptomic and proteomic counterparts, and a straightforward interpretation in terms of the underlying biochemical pathways will unavoidably fail. It is demonstrated that the comparative correlations analysis offers a way to exploit the observed correlations to obtain additional information about the physiological state of the system.

Animals↗

PubMed2006

Transcriptional profiling of Mycoplasma hyopneumoniae during iron depletion using microarrays.

Mycoplasma hyopneumoniae, the causative agent of swine enzootic pneumonia and a major component of the porcine respiratory disease complex, continues to confound swine producers despite control programmes worldwide. The disease is chronic and self-limiting, but the host is subject to immunopathological changes that potentiate respiratory disease associated with other pathogens. The response of M. hyopneumoniae to environmental stress is of interest because of its relevance to virulence mechanisms in other bacterial pathogens. One of these stressors, iron deprivation, is a prominent feature of the host innate immune response, and most certainly impacts growth of mycoplasmas in vivo. To study this, microarray technology was applied to the transcriptome analysis of M. hyopneumoniae during iron deprivation. An array consisting of 632 of the 698 ORFs in the genome was used to compare the mRNA isolated from organisms grown under normal laboratory conditions with that from organisms subjected to iron deprivation with the chelator 2,2'-dipyridyl. This analysis identified 27 genes that were either up- or down-regulated in response to low-iron growth conditions (P<0.01), with an estimated false discovery rate below 10 %. These included genes encoding transport proteins, enzymes involved in energy metabolism, and components of the translation process. Ten of the 27 identified genes had no assigned function. These studies indicate that M. hyopneumoniae can respond to changes in environmental conditions, but the mechanism employed remains unknown.

2,2'-Dipyridyl↗

PubMed2006

Global molecular and morphological effects of 24-hour chromium(VI) exposure on Shewanella oneidensis MR-1.

The biological impact of 24-h ("chronic") chromium(VI) [Cr(VI) or chromate] exposure on Shewanella oneidensis MR-1 was assessed by analyzing cellular morphology as well as genome-wide differential gene and protein expression profiles. Cells challenged aerobically with an initial chromate concentration of 0.3 mM in complex growth medium were compared to untreated control cells grown in the absence of chromate. At the 24-h time point at which cells were harvested for transcriptome and proteome analyses, no residual Cr(VI) was detected in the culture supernatant, thus suggesting the complete uptake and/or reduction of this metal by cells. In contrast to the untreated control cells, Cr(VI)-exposed cells formed apparently aseptate, nonmotile filaments that tended to aggregate. Transcriptome profiling and mass spectrometry-based proteomic characterization revealed that the principal molecular response to 24-h Cr(VI) exposure was the induction of prophage-related genes and their encoded products as well as a number of functionally undefined hypothetical genes that were located within the integrated phage regions of the MR-1 genome. In addition, genes with annotated functions in DNA metabolism, cell division, biosynthesis and degradation of the murein (peptidoglycan) sacculus, membrane response, and general environmental stress protection were upregulated, while genes encoding chemotaxis, motility, and transport/binding proteins were largely repressed under conditions of 24-h chromate treatment.

Bacterial Proteins↗

PubMed2003

Identification, timing, and signal specificity of Pseudomonas aeruginosa quorum-controlled genes: a transcriptome analysis.

There are two interrelated acyl-homoserine lactone quorum-sensing-signaling systems in Pseudomonas aeruginosa. These systems, the LasR-LasI system and the RhlR-RhlI system, are global regulators of gene expression. We performed a transcriptome analysis to identify quorum-sensing-controlled genes and to better understand quorum-sensing control of P. aeruginosa gene expression. We compared gene expression in a LasI-RhlI signal mutant grown with added signals to gene expression without added signals, and we compared a LasR-RhlR signal receptor mutant to its parent. In all, we identified 315 quorum-induced and 38 quorum-repressed genes, representing about 6% of the P. aeruginosa genome. The quorum-repressed genes were activated in the stationary phase in quorum-sensing mutants but were not activated in the parent strain. The analysis of quorum-induced genes suggests that the signal specificities are on a continuum and that the timing of gene expression is on a continuum (some genes are induced early in growth, most genes are induced at the transition from the logarithmic phase to the stationary phase, and some genes are induced during the stationary phase). In general, timing was not related to signal concentration. We suggest that the level of the signal receptor, LasR, is a critical trigger for quorum-activated gene expression. Acyl-homoserine lactone quorum sensing appears to be a system that allows ordered expression of hundreds of genes during P. aeruginosa growth in culture.

4-Butyrolactone↗

PubMed2004

Transcriptome analysis of the ArgR regulon in Pseudomonas aeruginosa.

Arginine metabolism in pseudomonads with multiple catabolic pathways for its utilization as carbon and nitrogen sources is of particular interest as the model system to study control of metabolic integration. We performed transcriptome analyses to identify genes controlled by the arginine regulatory protein ArgR and to better understand arginine metabolic pathways of P. aeruginosa. We compared gene expression in wild-type strain PAO1 with that in argR mutant strain PAO501 grown in glutamate minimal medium in the presence and absence of arginine. Ten putative transcriptional units of 28 genes were inducible by ArgR and arginine, including all known ArgR-regulated operons under aerobic conditions. The newly identified genes include the putative adcAB operon, which encodes a catabolic arginine decarboxylase and an antiporter protein, and PA0328, which encodes a hypothetical fusion protein of a peptidase and a type IV autotransporter. Also identified as members of the arginine network are the following solute transport systems: PA1971 (braZ) for branched-chain amino acids permease; PA2042 for a putative sodium:serine symporter; PA3934, which belongs to the family of small oligopeptide transporters; and PA5152-5155, which encodes components of an ABC transporter for a putative opine uptake system. The effect of arginine on the expression of these genes was confirmed by lacZ fusion studies and by DNA binding studies with purified ArgR. Only five transcriptional units of nine genes were qualified as repressible by ArgR and arginine, with three operons (argF, carAB, and argG) in arginine biosynthesis and two operons (gltBD and gdhA) in glutamate biosynthesis. These results indicate that ArgR is important in control of arginine and glutamate metabolism and that arginine and ArgR may have a redundant effect in inducing the uptake systems of certain compounds.

Arginine↗

PubMed2004

Molecular evidence for stem cell function of the slow-dividing fraction among human hematopoietic progenitor cells by genome-wide analysis.

The molecular mechanisms that regulate asymmetric divisions of hematopoietic progenitor cells (HPCs) are not yet understood. The slow-dividing fraction (SDF) of HPCs is associated with primitive function and self-renewal, whereas the fast-dividing fraction (FDF) predominantly proceeds to differentiation. CD34+/CD38- cells of human umbilical cord blood were separated into the SDF and FDF. Genomewide gene expression analysis of these populations was determined using the newly developed Human Transcriptome Microarray containing 51 145 cDNA clones of the Unigene Set-RZPD3. In addition, gene expression profiles of CD34+/CD38- cells were compared with those of CD34+/CD38+ cells. Among the genes showing the highest expression levels in the SDF were the following: CD133, ERG, cyclin G2, MDR1, osteopontin, CLQR1, IFI16, JAK3, FZD6, and HOXA9, a pattern compatible with their primitive function and self-renewal capacity. Furthermore, morphologic differences between the SDF and FDF were determined. Cells in the SDF have more membrane protrusions and CD133 is located on these lamellipodia. The majority of cells in the SDF are rhodamine-123dull. These results provide molecular evidence that the SDF is associated with primitive function and serves as basis for a detailed understanding of asymmetric division of stem cells.

ADP-ribosyl Cyclase↗

PubMed2026

Amaryllidaceae Alkaloids and Isoquinoline Alkaloids: A Perspective on Historical Approaches to Pathway Elucidation.

Alkaloid biosynthesis is a central topic in plant specialized metabolism because many alkaloids have ecological, pharmacological, and biotechnological relevance. Isoquinoline alkaloids (IAs) and Amaryllidaceae alkaloids (AAs) are both connected to aromatic amino acid metabolism, but they differ in taxonomic distribution, scaffold-forming chemistry, pathway resolution, and biotechnological development. This review compares the historical and methodological trajectories that have shaped IA and AA pathway elucidation, from compound isolation, radiotracer experiments, and biochemical inference to transcriptomics, metabolomics, functional enzymology, isotope-guided active-tissue identification, regulatory studies, and heterologous pathway reconstruction. In IAs, especially benzylisoquinoline alkaloids, broad genomic and transcriptomic resources have supported candidate gene discovery and functional characterization of several branches, including morphinan, protoberberine, benzophenanthridine, and aporphine-related pathways. In contrast, AA biosynthesis has advanced more recently through function-driven approaches that clarified key steps such as N4OMT-mediated 4'-O-methylation, NBS/NR-mediated norbelladine formation, CYP96T-dependent regioselective oxidative coupling, and transient reconstruction of major scaffold-forming branches. Remaining gaps include the unresolved enzymatic formation of 3,4-dihydroxybenzaldehyde in AAs and incomplete functional validation across less-studied IA scaffold classes. By integrating biochemical logic, omics-guided discovery, enzyme evolution, tissue specificity, regulation, and synthetic biology, this review identifies priorities for future alkaloid pathway discovery and sustainable production.

3,4-dihydroxybenzaldehyde↗

PubMed2004

A technical trick for studying proteomics in parallel to transcriptomics in symbiotic root-fungus interactions.

We have developed a protocol in which proteins and mRNA can be analyzed from single root samples. This experimental design was validated in arbuscular mycorrhiza by comparing the proteins profiles obtained with those from a classical protein extraction process. It is a step forward to make simultaneous proteome and transcriptiome profiling possible.

Electrophoresis, Gel, Two-Dimensional↗

PubMed2005

Comparative transcriptional profiling of two contrasting rice genotypes under salinity stress during the vegetative growth stage.

Rice (Oryza sativa), a salt-sensitive species, has considerable genetic variation for salt tolerance within the cultivated gene pool. Two indica rice genotypes, FL478, a recombinant inbred line derived from a population developed for salinity tolerance studies, and IR29, the sensitive parent of the population, were selected for this study. We used the Affymetrix rice genome array containing 55,515 probe sets to explore the transcriptome of the salt-tolerant and salt-sensitive genotypes under control and salinity-stressed conditions during vegetative growth. Response of the sensitive genotype IR29 is characterized by induction of a relatively large number of probe sets compared to tolerant FL478. Salinity stress induced a number of genes involved in the flavonoid biosynthesis pathway in IR29 but not in FL478. Cell wall-related genes were responsive in both genotypes, suggesting cell wall restructuring is a general adaptive mechanism during salinity stress, although the two genotypes also had some differences. Additionally, the expression of genes mapping to the Saltol region of chromosome 1 were examined in both genotypes. Single-feature polymorphism analysis of expression data revealed that IR29 was the source of the Saltol region in FL478, contrary to expectation. This study provides a genome-wide transcriptional analysis of two well-characterized, genetically related rice genotypes differing in salinity tolerance during a gradually imposed salinity stress under greenhouse conditions.

Base Sequence↗

PubMed2026

Proteogenomic features define subtypes of mantle cell lymphoma.

Mantle cell lymphoma (MCL) is a biologically heterogeneous B-cell malignancy. Although genomics and transcriptomics have delineated parts of the MCL disease spectrum, proteomics remains largely unexplored. Here, we conducted a comprehensive proteogenomic analysis integrating genomics, transcriptomics, and proteomics on peripheral blood samples from 27 patients with MCL and 4 healthy donors to investigate the translational and posttranslational dimensions of MCL. Our study identified 1296 downregulated and 468 upregulated proteins in MCL cells. The splicing pathways were significantly upregulated at both the mRNA and protein levels, suggesting a critical role for aberrant RNA splicing in MCL pathogenesis. Integration of proteomic data with genetic aberrations revealed immunoglobulin heavy chain variable mutational status and CCND1 mutation are associated with distinctive transcriptomic and proteomic profiles, which correspond to significant differences in clinical outcomes. A multiomics molecular stratification model incorporating proteomic data showed superior predictive power for patient survival compared with single-omics models (concordance index, 0.83 vs 0.74). This study provides, to our knowledge, the first comprehensive proteogenomic profile of MCL, offering novel insights into its molecular mechanisms and clinical behavior. The identification of molecular subtypes and prognostic protein signatures underscores the potential of proteomics to guide precision medicine strategies for MCL.

Humans↗

PubMed2026

Dual-transcriptomic analysis of human nasal transcriptome and microbiome reveals host-bacteria associations in symptomatic respiratory infection.

BACKGROUND: The human nasopharynx is colonized by a diverse community of commensal microbiota linked to many respiratory diseases, yet their associations with the host remain unclear. RESULTS: In this study, we introduced a dual-transcriptomics analysis strategy, which can characterize the host transcriptome and microbiome from nasal samples simultaneously. We applied this workflow to a local SARS-CoV-2 cohort with 76 asymptomatic infected patients, among whom 52 (68.42%) developed symptomatic infection during a 1-week follow-up period. Nasal swabs were collected from all 76 patients at enrollment and from 73 patients at one-week later follow-up. We detected a median of 8.94% reads that did not map to the human genome across all 149 samples, among which around half (median 49.68%) were successfully mapped to microbiome genome. Meta-transcriptomic analysis detected significantly higher SARS-related coronavirus loads in samples from the symptomatic group at enrollment (P = 0.004), and both groups showed decreased loads one week later (symptomatic, P = 0.001; asymptomatic, P = 0.035). Compared with benchmarking 16 S rRNA sequencing on 53 samples, our computational strategy showed high correlation of relative abundance in all top 20 genera (median Rho = 0.90, Pmax < 0.001). A total of 670 bacteria species were identified to show a relative abundance ≥ 0.01% in at least 10% samples. Differential abundance analysis identified 76 species (DASs) from six phyla with significantly decreased abundance in samples from the symptomatic group (log2(fold change or FC) < -1 and adjusted P < 0.05) compared to the asymptomatic group at enrollment. Integrating these symptom-associated DASs with host's gene expression using an expression quantitative trait bacteria (eQTB) model, we found 45 symptom-associated DASs identified at enrollment were significantly associated with one to 14 genes (adjusted P < 0.05). GSEA showed a series of symptom-associated DASs were significantly correlated with pathways related to olfactory function, keratinocyte differentiation, and DNA methylation. CONCLUSIONS: In summary, our dual-transcriptomic analysis strategy effectively characterized host-microbiome associations, offering insights into microbial contributions to respiratory diseases.

Humans↗

PubMed2006

An atlas of gene expression from seed to seed through barley development.

Assaying relative and absolute levels of gene expression in a diverse series of tissues is a central step in the process of characterizing gene function and a necessary component of almost all publications describing individual genes or gene family members. However, throughout the literature, such studies lack consistency in genotype, tissues analyzed, and growth conditions applied, and, as a result, the body of information that is currently assembled is fragmented and difficult to compare between different studies. The development of a comprehensive platform for assaying gene expression that is available to the entire research community provides a major opportunity to assess whole biological systems in a single experiment. It also integrates detailed knowledge and information on individual genes into a unified framework that provides both context and resource to explore their contributions in a broader biological system. We have established a data set that describes the expression of 21,439 barley genes in 15 tissues sampled throughout the development of the barley cv. Morex grown under highly controlled conditions. Rather than attempting to address a specific biological question, our experiment was designed to provide a reference gene expression data set for barley researchers; a gene expression atlas and a comparative data set for those investigating genes or regulatory networks in other plant species. In this paper we describe the tissues sampled and their transcriptomes, and provide summary information on genes that are either specifically expressed in certain tissues or show correlated expression patterns across all 15 tissue samples. Using specific examples and an online tutorial, we describe how the data set can be interrogated for patterns and levels of barley gene expression and how the resulting information can be used to generate and/or test specific biological hypotheses.

Databases, Genetic↗

PubMed2026

Loss of Function Dnmt3a Mutation Leads to Aberrant Neutrophil Migration.

Clonal hematopoiesis (CH), an age-related expansion of somatically mutated hematopoietic clones, is associated with increased risk of severe infections including coronavirus disease (COVID)-19, yet the underlying mechanisms remain unclear. Here, we investigated the impact of Dnmt3a deficiency in a murine model of influenza A virus (IAV) pneumonia. Dnmt3a-deficient mice exhibited increased pulmonary viral burden and reduced neutrophil accumulation in IAV-infected lungs despite comparable circulating neutrophil numbers. Functional analyses of neutrophils showed impaired chemotactic migration in vitro, whereas maturation, antimicrobial enzyme content, and metabolic capacity were unchanged. Transcriptomic profiling revealed downregulation of pathways involved in chemotaxis, cytokine signaling, and cellular activation, including reduced expression of Cxcr1. Supporting the translational relevance of these findings, proteomic analysis of plasma from individuals with germline DNMT3A mutations (Tatton-Brown-Rahman syndrome) revealed alterations in proteins associated with cell migration and cytoskeletal dynamics. Collectively, our findings demonstrate that Dnmt3a loss compromises innate immune defense by impairing neutrophil migration in a cell-intrinsic manner, leading to ineffective pathogen clearance. This work provides mechanistic insight into how CH-associated mutations contribute to age-associated susceptibility to infection and highlights altered leukocyte trafficking as a potential therapeutic target in aging populations with CH.

Animals↗

PubMed2025

Deleterious, protein-altering variants in GSPT2 are putatively associated with an X-linked neurodevelopmental disorder with intellectual disability, language impairment, autism, and epilepsy.

PURPOSE: Approximately 6% of individuals with neurodevelopmental disorders are predicted to be X-linked, and the GSPT2 gene, located at Xp11.22, has not yet been associated with any Mendelian disease. METHODS: To establish genotype-phenotype associations between GSPT2 and neurodevelopmental disorders, clinical investigations were performed in unrelated individuals, genomic and functional studies were conducted on the participants' blood and heterologous cell system. RESULTS: We described 6 individuals from 6 unrelated families carrying hemizygous variants in GSPT2 with intellectual disability, delayed speech and language development, autism spectrum disorder, epilepsy, or abnormal fetal neurodevelopment. Structural molecular modeling revealed significant deleterious effects of the identified variants. GSPT2 is preferentially enriched in the brain and cerebellum compared with other tissues. GSPT2-deficient H4 neuroglioma cells slow down the proliferation and downregulate the expression of cell-cycle-related genes. Transcriptomics revealed that GABAergic and calcium-signaling-related genes were significantly downregulated in GSPT2-deficient cells. Consistent with the transcriptomic data, RT-PCR analysis verified the marked downregulation of critical genes (CACNA1B, etc) in GSPT2-knockout cells and further confirmed these findings with proteomic profiling. CONCLUSION: Our data suggest a putative GSPT2-related X-linked neurodevelopmental disorders through dysregulation of cell-cycle progression and calcium/GABAergic signaling pathways.

Humans↗

PubMed2005

Applications of DNA tiling arrays for whole-genome analysis.

DNA microarrays are a well-established technology for measuring gene expression levels. Microarrays designed for this purpose use relatively few probes for each gene and are biased toward known and predicted gene structures. Recently, high-density oligonucleotide-based whole-genome microarrays have emerged as a preferred platform for genomic analysis beyond simple gene expression profiling. Potential uses for such whole-genome arrays include empirical annotation of the transcriptome, chromatin-immunoprecipitation-chip studies, analysis of alternative splicing, characterization of the methylome (the methylation state of the genome), polymorphism discovery and genotyping, comparative genome hybridization, and genome resequencing. Here we review different whole-genome microarray designs and applications of this technology to obtain a wide variety of genomic scale information.

Animals↗

PubMed2006

Helicobacter pylori HopH (OipA) and bacterial pathogenicity: genetic and functional genomic analysis of hopH gene polymorphisms.

BACKGROUND: Expression of the Helicobacter pylori outer membrane protein HopH is regulated by phase variation within a CT dinucleotide repeat motif of the hopH gene. METHODS: To investigate the importance of HopH for bacterial pathogenicity, we performed a detailed functional genomic and population-based genetic characterization of this contingency locus. RESULTS: Sequencing of hopH in H. pylori strains from 58 patients revealed that the hopH "on" genotype is linked to bacterial virulence determinants, such as the vacAs1, vacAm1, babA2, and, most strongly, cagA genotypes. hopH mutagenesis resulted in reduced bacterial adherence to gastric epithelia in vitro. Complementation of hopH in trans restored the adherence properties of hopH mutants. Although HopH has been previously linked to proinflammatory epithelial signaling, hopH mutagenesis did not alter epithelial interleukin-8 secretion in vitro. Comparative epithelial gene-expression profiling by cDNA microarrays revealed no significant differences between the wild-type-specific and hopH mutant-specific transcriptomes. By contrast, a large set of genes was differentially regulated in a cag pathogenicity island-dependent manner. CONCLUSION: An in-frame hopH gene may be linked to gastroduodenal diseases because of its association with other virulence factors or increased bacterial adherence and colonization. The strong linkage with cagA indicates that HopH may contribute to the fitness of cagA-positive strains in vivo.

Adhesins, Bacterial↗

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↗