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PubMed2006

Transcriptomics tool for the human Schistosoma blood flukes using microarray gene expression profiling.

We report the design, fabrication, and validation of a microarray covering the majority of the Schistosoma japonicum and Schistosoma mansoni transcriptomes. The oligonucleotide microarray contains 12,166 S. mansoni and 7055 S. japonicum target sequences. A confidence threshold of <or=0.001 (P value) was used in all analyses. The cross hybridization potential of the microarray was representative of 10,362 probes detected in both channels, while 12,052 probes hybridised to S. japonicum and 11,254 probes hybridised to S. mansoni. Differential hybridisation consisted of 3422 probes to S. mansoni mRNA and 3103 probes to S. japonicum mRNA. Important biological functions, such as transport, metabolism, immune evasion and host-parasite immunological interplay, cell communication, and sexual maturation are represented on this microarray. This is the first microarray commercially manufactured for studying schistosomes, and the large size and verified quality of the resource demonstrate its power for characterising the schistosome transcriptome.

Animals↗

PubMed2005

Yeast HAT1 and HAT2 deletions have different life-span and transcriptome phenotypes.

HAT-B is a yeast histone acetyltransferase composed of Hat1, Hat2 and Hif1 proteins. We demonstrate that a hat2 mutant or a hat1hat2 double mutant, but not a hat1 mutant, have an extended life-span. Transcriptome analysis shows that the single hat mutants are not very different from wild type. However, the comparison of the hat1 and hat2 transcriptomes shows that they are different. The hat1hat2 double mutant shows a transcriptional phenotype similar to that of the hat1 mutant but strongly enhanced. These results indicate that Hat2p could have additional functions in the cell to those of Hat1p.

Acetyltransferases↗

PubMed2006

Transcriptome analysis of Neotyphodium and Epichloë grass endophytes.

Large-scale gene discovery has been performed for the grass fungal endophytes Neotyphodium coenophialum, Neotyphodium lolii, and Epichloë festucae. The resulting sequences have been annotated by comparison with public DNA and protein sequence databases and using intermediate gene ontology annotation tools. Endophyte sequences have also been analysed for the presence of simple sequence repeat and single nucleotide polymorphism molecular genetic markers. Sequences and annotation are maintained within a MySQL database that may be queried using a custom web interface. Two cDNA-based microarrays have been generated from this genome resource. They permit the interrogation of 3806 Neotyphodium genes (Nchip microarray), and 4195 Neotyphodium and 920 Epichloë genes (EndoChip microarray), respectively. These microarrays provide tools for high-throughput transcriptome analysis, including genome-specific gene expression studies, profiling of novel endophyte genes, and investigation of the host grass-symbiont interaction. Comparative transcriptome analysis in Neotyphodium and Epichloë was performed.

Computational Biology↗

PubMed2005

Analysis of the biliary transcriptome in experimental biliary atresia.

BACKGROUND & AIMS: Discovery of the pathogenic mechanisms of biliary atresia has been limited by the inability to study extrahepatic biliary tissues from patients at early phases of disease. Here, we used a rotavirus-induced model of biliary atresia to investigate the entire biliary transcriptome for molecular networks activated at the onset and different phases of progression to duct obstruction. METHODS: We injected Balb/c mice with saline or rotavirus intraperitoneally within 24 hours of birth, microdissected the gallbladder and extrahepatic bile ducts en bloc 3, 7, and 14 days later, generated biotinylated RNA pools, and hybridized them against microarrays containing 45,101 gene products. RESULTS: Data filtering, cluster analysis, and functional assignment of the gene expression platform revealed 2 unique patterns of expression. The first was an overarching expression of genes regulating immunity, enzymes, and structural proteins at all phases of atresia. Within this pattern, the sequential expression of the interferon inducers Irf7 and Irf9 at the onset of injury, and interferon-gamma and interferon-gamma-activated genes (Stat1, Igtp, Cxcl9, Cxcl10) at the time of duct obstruction, pointed to a prominent proinflammatory circuit. The second was the time-restricted expression of genes regulating biological networks previously unrecognized in biliary atresia, such as the complement components C3ar-1 and C1q-alpha/beta. CONCLUSIONS: The coordinate expression of functionally related genes in the biliary transcriptome underscores a predominant proinflammatory footprint and provides a basis for identification of gene groups that may play regulatory roles in the pathogenesis of duct injury and obstruction in experimental biliary atresia.

Animals↗

PubMed2006

A transcriptomic approach of salinity response in the euryhaline teleost, Dicentrarchus labrax.

Euryhaline teleosts possess the capacity to osmoregulate under various environmental conditions (freshwater to hypersaline water). This physiological capacity is generally monitored using enzyme activity assays (Na+/K+ -ATPase...), hormones quantification (prolactine, growth hormone) or their mRNAs expression. To date, few studies addressed the genetic correlates of adaptation to varying salinity at a molecular level in such fish. In the sea bass Dicentrarchus labrax, genetic differentiation was observed at specific allozyme loci between lagoon- and open-sea populations. In the present study, we investigated transcriptomic response of D. labrax to salt- and freshwater acclimation in two organs involved in osmoregulation, gill and intestine. By using suppression subtractive hybridisation, we characterised 586 partial cDNA sequences encoding proteins potentially involved in the metabolism of sea bass acclimated to salt- or freshwater under experimental conditions. Using these results, we first characterised complete genomic sequence of a carbonic anhydrase and then analysed mRNA expression of genes potentially involved in osmoregulation mechanisms (Na+/K+ -ATPase, carbonic anhydrase, angiotensin-converting enzyme and claudin-3), cell-cycle regulation (secretagogin) and immune system (nephrosin) in gill and intestine of wild fish from open sea and lagoons. Our analyses indicate a strong tissue- and environmental-dependant expression pattern for all the genes studied. A transcriptomic approach such as described in the present paper provides thus a first description of genes involved in metabolic or structural functions important for coping with environmental salinity variations in a euryhaline fish like the common sea bass D. labrax. It should be supplemented by proteomics to check the direct involvement of the gene products at the protein level, and by polymorphism analyses if one is to understand population or individual fluctuations in acclimation to salinity variation.

Adaptation, Physiological↗

PubMed2004

An insight into the salivary transcriptome and proteome of the adult female mosquito Culex pipiens quinquefasciatus.

To obtain an insight into the salivary transcriptome and proteome (sialome) of the adult female mosquito Culex quinquefasciatus, a cDNA library was randomly sequenced, and aminoterminal information for selected proteins and peptides was obtained. cDNA sequence clusters coding for secreted proteins were further analyzed. The transcriptome revealed messages coding for several proteins of known families previously reported in the salivary glands of other blood-feeding insects as well as immune-related products such as C-type lectin, gambicin, and members of the prophenol oxidase cascade. Additionally, several transcripts coding for low-complexity proteins were found, some clearly coding for mucins. Many novel transcripts were found, including a novel endonuclease previously described in crabs and shrimps but not in insects; a hyaluronidase, not described before in mosquito salivary glands but found in venom glands and in salivary glands of sand flies and black flies; several cysteine-rich peptides with possible anticlotting function, including one similar to a previously described nematode family of anti-proteases; and a completely novel family of cysteine- and tryptophane-rich proteins (CWRC family) for which 12 full-length sequences are described. Also described are 14 additional novel proteins and peptides whose function and/or family affiliation are unknown. In total, 54 transcripts coding for full-length proteins are described. That several of these are translated into proteins was confirmed by finding the corresponding aminoterminal sequences in the SDS-PAGE/Edman degradation experiments. Electronic versions of all tables and sequences can be found at http://www.ncbi.nlm.nih.gov/projects/Mosquito/C_quinquefasciatus_sialome.

Amino Acid Sequence↗

PubMed2005

Analysis of the growth phase-associated transcriptome of Streptococcus pyogenes.

Streptococcus pyogenes (group A streptococci, GAS) is a human pathogen which probably varies its multiplication rate and thus, growth phases in association with the type of infection caused in its host. To create a basis for future determinations of such associations, the genome-wide growth phase-related GAS transcriptome was assessed in the present study. Therefore, the published serotype M1 S. pyogenes genome sequence as well as the partially sequenced serotype M18 and M49 GAS genomes were used to produce DNA microarrays that carried 2256 oligonucleotide probes matching 3662 open reading frames (ORFs). With these microarrays, the transcriptome of the serotype M49 GAS strain 591 grown to the exponential, transition, and early stationary growth phases was assessed in seven independent experiments. The gained data were compared to real-time RT-PCR assays. Data analysis was refined by a novel approach, i.e. grouping of expressed genes to four classes according to relative transcript abundance and gene functions. At the different growth phases, 86.7%, 79.5% and 55.7% of the at least 1883 ORFs contained in the serotype M49 genome were expressed above the defined detection level. Contrary to the general trend, transcript amounts of genes in the functional groups of transport and membrane proteins as well as stress response factors peaked at the transition phase. The most prominent changes in the transcript abundances were predominantly observed for sugar compound transport and turnover-related ORFs. The majority of known virulence genes had their maximum expression during the transition phase, consistent with the proposed associated change in virulence behavior of the bacteria. With these results, it will now be feasible to assess the in situ growth phase of a given GAS strain during any type of infection by measuring the expression of selected marker genes.

DNA, Bacterial↗

PubMed2026

Multi-omics and spatial transcriptomics reveal that S100A10 drives CD8+ T-cell exhaustion and immune evasion in hepatocellular carcinoma through cPLA2-5-LOX-mediated arachidonic acid metabolism and ferroptosis.

Immune evasion in hepatocellular carcinoma (HCC) represents a major biological barrier limiting the efficacy of immunotherapy, yet its molecular basis remains incompletely understood. Increasing evidence indicates that tumor metabolic reprogramming and ferroptosis-related signaling play critical roles in shaping an immunosuppressive tumor microenvironment (TME); however, the specific regulatory factors involved remain unclear. This study aims to systematically elucidate the functional role of S100 calcium-binding protein A10 (S100A10) in immune evasion in HCC, with a particular focus on the molecular mechanisms by which S100A10 regulates CD8+ T-cell exhaustion through arachidonic acid (AA) metabolism and ferroptosis, as well as its potential therapeutic implications. To this end, data from The Cancer Genome Atlas Liver Hepatocellular Carcinoma (TCGA-LIHC) cohort are integrated to analyze the expression patterns of S100A10, its prognostic value, and its association with the immune microenvironment. S100A10 overexpression and knockout models are established in HCCLM3 and MHCC97L cell lines, and S100A10-mediated metabolic pathway reprogramming is characterized using transcriptomic profiling, untargeted metabolomics, and ferroptosis-related functional assays. In parallel, single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics are employed to delineate the cell-type specificity and spatial distribution of S100A10. Furthermore, human CD8+ T-cell co-culture systems and orthotopic mouse HCC models are used to evaluate the impact of S100A10 on immune function and responsiveness to anti-programmed cell death protein 1 (anti-PD-1) therapy. The results demonstrate that S100A10 is significantly upregulated in HCC and is closely associated with poor prognosis and an immunosuppressive state. Mechanistically, S100A10 activates cytosolic phospholipase A2-arachidonate 5-lipoxygenase (cPLA2-5-LOX)-mediated AA oxidative metabolism, leading to the accumulation of lipid peroxidation products and ferroptosis-associated signals, thereby driving CD8+ T-cell exhaustion and promoting immune evasion. Significantly, inhibition of S100A10 reshapes the tumor immune microenvironment (TIME) and enhances the therapeutic efficacy of anti-PD-1 treatment. Collectively, these findings identify S100A10 as a critical regulator of metabolic-immune coupling in HCC and provide a theoretical basis for combinatorial strategies targeting metabolism and immunotherapy.

Arachidonic acid metabolism↗

PubMed2026

Single-nucleus transcriptomics reveals cell type-specific remodeling and epilepsy-associated microglia.

Temporal lobe epilepsy (TLE) is the most common acquired epilepsy, causing refractory seizures and cognitive deficits. We performed single-nucleus RNA sequencing on hippocampal tissue from mice 3 and 6 weeks following pilocarpine-induced status epilepticus, a robust model of TLE. Epilepsy samples showed reductions in Cck and Lamp5-Lhx6 interneuron subclusters, alongside increases in Cajal-Retzius cells, dentate granule (DG) cell precursors, and a mature DG cell subcluster. Among glia, an astrocyte subcluster and a markedly expanded microglia sublcuster were increased. We term this microglia population epilepsy-associated microglia (EAM). The transcriptomic profile of EAM overlaps with microglia described in models of Alzheimer's disease and traumatic brain injury, including enrichment of Myo1e and Igf1. EAM display amoeboid morphology, can be found in clumps around pyramidal and granule cell body layers, and exhibit enlarged vesicles and mitochondria. Cell-cell interaction analysis predicts DG cells as their primary interaction partners. This dataset defines transcriptomic programs underlying key cellular alterations in TLE, enabling mechanistic dissection of epileptogenesis.

TLE↗

PubMed2026

Genomic and transcriptomic features of relapsed small cell lung cancer.

BACKGROUND: Relapsed small cell lung cancer is characterized by treatment resistance and poor outcomes. Genomic and transcriptomic alterations in relapsed SCLC have not been characterized well. We comprehensively profiled relapsed SCLC samples along with patient-matched treatment-naive samples, when available, using whole-exome (WES), whole-genome (WGS), and RNA-sequencing (RNA-seq) to describe the molecular landscape of relapsed SCLC. Our goal is to identify potential novel pathways for additional functional validation and eventually novel therapeutic options. METHODS: We analyzed 54 relapsed and 27 treatment-naive SCLC samples using WES (with 26 patient-matched paired samples). A subset of the samples was also analyzed by WGS (n=28) and RNA-seq (n=31). Differences in mutational signatures, gene expression, structural variants, splicing, and neoantigen profiles at diagnosis and relapse were investigated. RESULTS: Relapsed SCLC samples demonstrated mutation signatures characteristic of platinum and APOBEC mutagenesis. Furthermore, these samples were characterized by MYC, MYCL and MYCN amplifications. Both treatment-naive and relapsed SCLC samples showed high prevalence of mutation-associated neoantigens (median= 86 in treatment-naive and 90 in relapsed SCLC; p=0.8) and TP53 was the most frequently altered gene to result in a neoantigen (48% of analyzed samples). Potential mechanisms of immune evasion, including amplification of CD24, overexpression of IDO1, increased M2 macrophage presence, and upregulation of HLA-E were also observed in relapse samples. Differences in alternative splicing patterns were observed between treatment-naive and relapsed small cell samples. Retained intron events were significantly enriched in treatment-naive samples and affected genes involved in DNA repair, metabolism, and WNT and MYC pathways. CONCLUSIONS: This study highlights the genomic and transcriptomic features of relapsed SCLC. These samples were characterized by genomic instability, WNT and MYC dysregulation, and splicing aberrations. Additional studies targeting the splicing machinery, WNT signaling, and immune evasion pathways could identify novel therapeutic vulnerabilities in SCLC.

Journal Article↗

PubMed2006

Transcriptome analyses of male germ cells with serial analysis of gene expression (SAGE).

Serial analysis of gene expression (SAGE) provides an alternative with additional advantages to microarrays for studying gene expression during spermatogenesis. The digitized transcriptome provided by SAGE of purified mouse germ cells identified 27,504 species of transcripts expressed in type A spermatogonia, pachytene spermatocytes, and round spermatids. Over 2700 of these transcripts were novel. Computational analyses allowed the identification of clusters of co-regulated genes, cell-specific promoter modules, cell-specific biological processes, as well as "preferential" biological networks in different cell types. These analyses provided potential drug targets for interference of specific pathways at different stages of spermatogenesis. Analyses of the transcriptomes revealed the prominent role of cytochrome c oxidase in germ cells and suggest a novel role for this enzyme in cytochrome c-mediated apoptosis in spermatogonia. A number of genes were shown to undergo differential splicing during spermatogenesis giving rise to cell-specific splice variants.

Alternative Splicing↗

PubMed2006

Cerebellar 'transcriptome' reveals cell-type and stage-specific expression during postnatal development and tumorigenesis.

Disorders of cerebellar development can result in neurological disease and cancer. The identity of transcription factors that may uniquely mark and/or regulate development of single cerebellar cell types, however, is poorly understood. We used a library of approximately 1100 probes for expression of transcription factor (TF)-encoding genes (>70% of the mammalian 'transcriptome') to identify 227 genes with expression in developing neuronal and glial populations and 24 TFs that show cell-type- and stage-specific expression in granule cells, Purkinje cells and interneurons during postnatal cerebellar development. The utility of this panel is exemplified by analysis of medulloblastoma that shows upregulation of markers specific for early granule cell lineage, but not for other neuronal cell types, indicative of a unipotent precursor as well as a block in granule cell differentiation within the tumor. We propose that this atlas of the cerebellar transcriptome and the panel of 24 validated markers will be generally useful in analyses of mutations affecting postnatal cerebellar development and neoplasia.

Animals↗

PubMed2006

Salmonella transcriptomics: relating regulons, stimulons and regulatory networks to the process of infection.

The advent of Salmonella transcriptomics has heralded a new era for gene expression analysis of this formidable intracellular pathogen. Increasing numbers of Salmonella transcriptomic datasets will contribute to the comprehensive definition of regulons, stimulons and regulatory networks. This task has highlighted the need for sophisticated computational techniques to describe regulatory interactions.

Adaptation, Physiological↗

PubMed2005

An oligonucleotide microarray for transcriptome analysis of Schistosoma mansoni and its application/use to investigate gender-associated gene expression.

Global profiling transcriptomes of parasitic helminths offers the potential to simultaneously identify co-ordinately expressed genes, novel genetic programs and uniquely utilized metabolic pathways, which together provide an extensive and new resource for vaccine and drug discovery. We have exploited this post-genomic approach to fabricate the first oligonucleotide DNA microarray for gene expression analysis of the parasitic trematode Schistosoma mansoni. A total of 17,329 S. mansoni DNA sequences were used to design a microarray consisting of 7335 parasite elements or approximately 50% of this parasite's transcriptome. Here, we describe the design of this new microarray resource and its evaluation by extending studies into gender-associated gene expression in adult schistosomes. We demonstrate a high degree of reproducibility in detecting transcriptional differences among biologically replicated experiments and the ability of the microarray to distinguish between the expression of closely related gene family members. Importantly, for issues related to sexual dimorphism, labour division, gamete production and drug target discovery, 197 transcripts demonstrated a gender-biased pattern of gene expression in the adult schistosome, greatly extending the number of sex-associated genes. These data demonstrate the power of this new resource to facilitate a greater understanding into the biological complexities of schistosome development and maturation useful for identifying novel intervention strategies.

Animals↗

PubMed2005

Insights into the P. y. yoelii hepatic stage transcriptome reveal complex transcriptional patterns.

During their complex life cycle, malaria parasites adopt morphologically, biochemically and immunologically distinct forms. The intra-hepatic form is the least known, yet of established value in the induction of sterile immunity and as a target for chemoprophylaxis. Using Plasmodium yoelii as a model we present here a novel approach to the elucidation of the transcriptome of this poorly studied stage. Sequences from Plasmodium were obtained in 388 of the 3533 inserts (11%) isolated from liver stages cDNA obtained from optimized cultures with high yields. These corresponded to a total of 88 putative P. yoelii genes. The majority of the transcribed genes identified, code for predicted proteins of as yet unknown function. The RT-PCR analysis carried out for 29 of these genes, confirmed expression at the hepatic stage and provided evidence for complex patterns of genes transcription in the distinct stages found in the mosquito and vertebrate host. The results demonstrate the efficacy of the approach that can now be applied to further detailed analysis of the hepatic stage transcriptome of Plasmodium.

Animals↗

PubMed2006

Transcriptomic comparison of two Entamoeba histolytica strains with defined virulence phenotypes identifies new virulence factor candidates and key differences in the expression patterns of cysteine proteases, lectin light chains, and calmodulin.

The availability of Rahman, and the virulent HM-1:IMSS strain of E. histolytica, provides a powerful tool for identifying virulence factors of E. histolytica. Here we report an attempt to identify potential virulence factors of E. histolytica by comparing the transcriptome of E. histolytica HM-1:IMSS and E. histolytica Rahman. With phenotypically defined strains, we compared the transcriptome of Rahman and HM-1:IMSS using a custom 70mer oligonucleotide based microarray that has essentially full representation of the E. histolytica HM-1:IMSS genome. We find extensive differences between the two strains, including distinct patterns of gene expression of cysteine proteinases, AIG family members, and lectin light chains.

Animals↗

PubMed2006

Transcriptome analysis reveals the population of dendritic RNAs and their redistribution by neural activity.

Subcellular localization of RNA is an efficient way to localize proteins to a specific region of a cell. The dendritic localization of RNAs underlies the establishment and maintenance of the synaptic functions of neuronal cells. A requirement for dendritic RNA localization and subsequent local translation has been demonstrated in several forms of experience-dependent synaptic plasticity. In spite of several attempts to identify these RNAs, the population of RNA species present in dendrites as a whole has not been well described. Here we show the results of microarray analyses with RNAs isolated from heavy portion of polysome (HP) fraction where RNA granules are enriched in and synaptosome fraction, prepared from the rat brain. These analyses revealed the complex nature of the dendritic RNA population, which included RNAs that were not expected to be in the dendrites. Neural activity caused by an electroconvulsive shock triggered a redistribution of the population of dendritic transcriptome towards the area of overlap between the HP and the synaptosome, which is assumed to be neck of spine. This redistribution may accompany some changes in the translatability of those transcriptome, which suggests complex mechanisms of local translation in response to synaptic inputs.

Animals↗

PubMed2005

Functional Genomics meets neurodegenerative disorders Part I: transcriptomic and proteomic technology.

Transcriptomics and proteomics are increasingly applied to gain a mechanistic insight into neurodegenerative disorders. These techniques not only identify distinct, differentially expressed mRNAs and proteins but are also employed to dissect signaling pathways and reveal networks by using an integrated approach. In part I of this back-to-back review, technical aspects are discussed: in the transcriptomics section, which includes enrichment by laser microcapture dissection, we comment on qRT-PCR, SAGE, subtractive hybridization, differential display and microarrays, including software packages. In the proteomics section we discuss two-dimensional (2D) gel electrophoresis, liquid chromatography, methods to label and enrich specific proteins or peptides, and different types of mass spectrometers. These tools have been applied to a range of neurodegenerative disorders and are discussed and integrated in part II (Functional Genomics meets neurodegenerative disorders. Part II: application and data integration).

Animals↗