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PubMed2025

Staphylococcus aureus COL: An Atypical Model Strain of MRSA That Exhibits Slow Growth and Antibiotic Tolerance due to a Mutation in PRPP Synthetase.

Methicillin-resistant Staphylococcus aureus (MRSA) has been a pathogen of global concern since its emergence in the 1960s. As one of the first MRSA strains isolated, COL has become a common model strain of S. aureus. Here we report that COL is, in fact, an atypical strain of MRSA that exhibits slow growth and multidrug tolerance. Genomic analysis identified three mutated genes in COL (rpoB, gltX and prs) with links to tolerance. Allele swapping experiments between COL and the closely-related, nontolerant Newman strain uncovered a complex interplay between these genes. However, Prs (phosphoribosyl pyrophosphate [PRPP] synthetase) accounted for most of the growth and tolerance phenotype of COL. Biochemical and transcriptomic analysis revealed that COL does not exhibit slow growth as a result of partial stringent response activation, as previously proposed. Instead, the COL Prs mutation greatly reduces the PRPP synthetase activity of the enzyme and leads to downregulation of pyrimidine, histidine, and tryptophan synthesis, three pathways that rely on PRPP. Overall, our findings indicate that COL is an atypical, antibiotic-tolerant strain of MRSA whose isolation predates the previous first report of tolerance among clinical isolates. Characterization of clinical Prs mutations and their relationship with tolerance requires further investigation.

Methicillin-Resistant Staphylococcus aureus↗

PubMed2026

Muscular fiber properties and multi-omics investigation of larval and adult locomotor muscle in Microhyla fissipes.

During metamorphosis, Microhyla fissipes undergoes a critical transition from an aquatic to a terrestrial lifestyle, accompanied by significant remodeling of skeletal muscle. Notably, larval tail muscle degenerates, while adult hindlimb muscle develops. However, the molecular mechanisms that orchestrate these muscle type-specific adaptations to the changing environment remain unclear. In this study, histological observation, transcriptomics, and metabolomics were integrated to compare locomotor muscles from two stages: larval muscle from tail versus adult muscle from hindlimb. Our results revealed that adult muscle fibers exhibited reduced diameter and shorter sarcomere length compared to those of tadpoles. Transcriptomic analysis identified 4103 differentially expressed genes (DEGs), including 2182 up-regulated and 1921 down-regulated genes. Up-regulated genes were mainly involved in energy metabolism and cellular homeostasis pathways, including PPAR signaling and oxidative phosphorylation, whereas down-regulated genes were associated with carbohydrate metabolism and cell proliferation pathways, such as glycolysis/gluconeogenesis and PI3K-Akt signaling. Metabolic profiling indicated a metabolic shift from anaerobic to aerobic energy production, with 57 differential metabolites identified, mainly involved in protein metabolism and insulin-related pathways. Integrated multi-omics analysis further highlighted the AMPK and FoxO signaling pathways play key roles in this process. In conclusion, our findings demonstrate that the metabolic and structural differences between larval and adult skeletal muscles are mediated by AMPK- and FoxO-dependent signaling pathways, providing novel insights into the molecular mechanisms underlying adaptive development and locomotor transition in anuran amphibians.

Animals↗

PubMedDate not supplied

Elucidation of the effect of brain cortex tetrapeptide Cortagen on gene expression in mouse heart by microarray.

OBJECTIVES: Aging is associated with significant alterations in gene expression in numerous organs and tissues. Anti-aging therapy with peptide bioregulators holds much promise for the correction of age-associated changes, making a screening for their molecular targets in tissues an important question of modern gerontology. The synthetic tetrapeptide Cortagen (Ala-Glu-Asp-Pro) was obtained by directed synthesis based on amino acid analysis of natural brain cortex peptide preparation Cortexin. In humans, Cortagen demonstrated a pronounced therapeutic effect upon the structural and functional posttraumatic recovery of peripheral nerve tissue. Importantly, other effects were also observed in cardiovascular and cerebrovascular parameters. DESIGN: Based on these latter observations, we hypothesized that acute course of Cortagen treatment, large-scale transcriptome analysis, and identification of transcripts with altered expression in heart would facilitate our understanding of the mechanisms responsible for this peptide biological effects. We therefore analyzed the expression of 15,247 transcripts in the heart of female 6-months CBA mice receiving injections of Cortagen for 5 consecutive days was studied by cDNA microarrays. RESULTS: Comparative analysis of cDNA microarray hybridisation with heart samples from control and experimental group revealed 234 clones (1,53% of the total number of clones) with significant changes of expression that matched 110 known genes belonging to various functional categories. Maximum up- and down-regulation was +5.42 and -2.86, respectively. CONCLUSION: Intercomparison of changes in cardiac expression profile induced by synthetic peptides (Cortagen, Vilon, Epitalon) and pineal peptide hormone melatonin revealed both common and specific effects of Cortagen upon gene expression in heart.

Animals↗

PubMed2025

Integrating necroptosis and immune landscapes: a multi-omics-derived NecropImmScore stratifies prognosis and therapy in ovarian cancer.

BACKGROUND: Ovarian cancer (OC) remains the deadliest gynecologic malignancy, largely due to its immunosuppressive tumor microenvironment (TME) and resistance to therapy. Necroptosis, a regulated lytic cell death pathway mediated by the RIPK1-RIPK3-MLKL axis, can trigger immunogenic cell death, but its specific role in shaping the OC immune landscape and its clinical translation potential are posorly understood. METHODS: We employed multi-omics analysis (transcriptomics, genomics, clinical data) from TCGA-OV (n = 380), ICGC OV-AU, and IMvigor210 cohorts, combined with rigorous in vitro functional validation using OC cell lines (SKOV3, HEY), macrophages (THP-1 derived), and T cells (Jurkat). Computational immunology approaches (ESTIMATE, CIBERSORT, ssGSEA) quantified immune infiltration. We identified MLKL-associated immune genes, performed survival analysis (Kaplan-Meier, Cox regression), and constructed a necroptosis-immune signature (NecropImmScore) using consensus clustering and PCA of 102 prognostic genes. Drug sensitivity was predicted via pRRophetic and CellMiner. RESULTS: MLKL emerged as a protective prognostic biomarker (p = 0.018), significantly correlated with enhanced immune infiltration (ImmuneScore, StromalScore, ESTIMATEScore; p < 2.22e-16), M1 macrophage polarization (p = 0.006), activated CD4 + T cells (p = 0.003), and elevated immune checkpoint expression (PD-L1, CTLA4, LAG3, TIGIT). In vitro, MLKL overexpression in OC cells promoted M1 polarization (p < 0.05), activated Jurkat T cells (upregulated CCR4/5/7/9, CD69, CD3D/E, GZMB; p < 0.05), and induced key chemokines (CXCL9/10/11/13) critical for immune cell recruitment. Integration of MLKL-related and immune-related DEGs (n = 632) revealed enrichment in T-cell activation, chemokine signaling, and antigen presentation pathways (FDR < 0.05). Consensus clustering based on 102 survival-associated genes defined three molecular subtypes (Clusters A-C) with divergent survival (p = 0.019), necroptosis activity, and immune infiltration (Cluster C: best prognosis, highest MLKL/ImmuneScore). The derived NecropImmScore robustly stratified patients: high-score correlated with superior overall survival (TCGA: p < 0.001; ICGC: p = 0.014), inflamed TME phenotype, elevated checkpoint expression, and improved response to anti-PD-L1 in IMvigor210. Critically, high NecropImmScore predicted higher BRCA1 mutation frequency (AUC = 0.802), synergy with BRCA1 status for prognosis, higher homologous recombination deficiency (HRD) score, sensitivity to cisplatin (p = 0.014), paclitaxel (p = 0.016), gemcitabine (p = 0.017), and provided superior prognostic stratification when combined with TMB and HRD score (p < 0.001). CONCLUSION: This study establishes MLKL as a master regulator of anti-tumor immunity in OC, driving chemokine-mediated immune cell recruitment and TME reprogramming. The novel NecropImmScore is a multifaceted biomarker that effectively predicts prognosis, immunotherapy response, BRCA1 deficiency, and chemosensitivity, offering significant potential for guiding precision therapeutic strategies in OC.

Humans↗

PubMed2026

Nitric oxide enhances SlSPL10-mediated transcriptional repression of carotenoid synthesis genes to delay tomato fruit carotenoid accumulation.

Nitric oxide (NO) inhibits climacteric fruit ripening, but its mechanisms remain elusive. Here, S-nitrosoglutathione (GSNO, a NO donor) reduces carotenoid accumulation in tomato fruit, confirming NO's role as carotenoid biosynthesis suppressor. Transcriptome analysis identified SlSPL10 (SQUAMOSA promoter binding protein-like 10) as a key player during this process. Genetic evidence further revealed that SlSPL10 negatively regulates carotenoid synthesis. Moreover, GSNO fails to suppress carotenoid synthesis in slspl10 mutant fruit, in contrast to wild-type fruit, highlighting the involvement of SlSPL10 in NO-inhibited carotenoid synthesis. Transcriptomic profiling of slspl10 mutant fruit showed that both NO and SlSPL10 regulate key carotenoid synthesis genes (SlGPS, SlPDS, SlZDS, SlZISO, and SlCRTISO). SlSPL10 directly binds to the promoters of these genes to repress their transcription, and NO enhances the transcriptional inhibition of SlGPS, SlZISO, and SlCRTISO. These three genes are indispensable for SlSPL10's role in NO-mediated carotenoid suppression. Collectively, NO enhances SlSPL10-mediated repression of carotenoid biosynthesis gene expression, reducing carotenoid accumulation in tomato fruit.

Solanum lycopersicum↗

PubMed2004

Gene expression profiles in the rat streptococcal cell wall-induced arthritis model identified using microarray analysis.

Experimental arthritis models are considered valuable tools for delineating mechanisms of inflammation and autoimmune phenomena. Use of microarray-based methods represents a new and challenging approach that allows molecular dissection of complex autoimmune diseases such as arthritis. In order to characterize the temporal gene expression profile in joints from the reactivation model of streptococcal cell wall (SCW)-induced arthritis in Lewis (LEW/N) rats, total RNA was extracted from ankle joints from naive, SCW injected, or phosphate buffered saline injected animals (time course study) and gene expression was analyzed using Affymetrix oligonucleotide microarray technology (RAE230A). After normalization and statistical analysis of data, 631 differentially expressed genes were sorted into clusters based on their levels and kinetics of expression using Spotfire profile search and K-mean cluster analysis. Microarray-based data for a subset of genes were validated using real-time PCR TaqMan analysis. Analysis of the microarray data identified 631 genes (441 upregulated and 190 downregulated) that were differentially expressed (Delta > 1.8, P < 0.01), showing specific levels and patterns of gene expression. The genes exhibiting the highest fold increase in expression on days -13.8, -13, or 3 were involved in chemotaxis, inflammatory response, cell adhesion and extracellular matrix remodelling. Transcriptome analysis identified 10 upregulated genes (Delta > 5), which have not previously been associated with arthritis pathology and are located in genomic regions associated with autoimmune disease. The majority of the downregulated genes were associated with metabolism, transport and regulation of muscle development. In conclusion, the present study describes the temporal expression of multiple disease-associated genes with potential pathophysiological roles in the reactivation model of SCW-induced arthritis in Lewis (LEW/N) rat. These findings improve our understanding of the molecular events that underlie the pathology in this animal model, which is potentially a valuable comparator to human rheumatoid arthritis (RA).

Animals↗

PubMed2026

Paired analysis of primary adenoid cystic carcinoma and derived cell lines reveals a mesenchymal and stem-like shift associated with therapy resistance.

Adenoid cystic carcinoma (ACC) is a salivary gland malignancy characterized by slow but persistent growth, frequent local recurrence, and late metastatic progression. Patients with unresectable, recurrent, or metastatic disease have limited therapeutic options. Efforts to identify effective therapeutic targets have been hindered by the limited availability of well-characterized ACC models. In this study, we established 11 ACC cell lines and performed RNA sequencing of nine cell lines and their matched primary tumors to evaluate the preservation and evolution of molecular and lineage-associated characteristics during cell line establishment. Comparative transcriptomic analysis revealed reduced epithelial and luminal differentiation programs in the cell lines, accompanied by enrichment of myoepithelial, EMT-, and cancer stem cell-associated transcriptional programs. Digital deconvolution and single-sample gene set enrichment analysis supported enrichment of hybrid EMT/stem-like states during in vitro propagation, while comparison with publicly available primary-recurrent ACC data demonstrated partial preservation of recurrence-associated plasticity and invasion programs. Protein-level validation of representative epithelial, myoepithelial, EMT, and stemness markers supported the major transcriptomic changes. In addition, a cell line with a higher stemness signature showed reduced sensitivity to cisplatin. Together, these findings indicate that ACC cell line establishment is associated with transcriptional reprogramming and enrichment of plastic, EMT/stem-like states while retaining selected ACC lineage characteristics. These models provide experimentally tractable platforms for investigating ACC progression, therapeutic response, and mechanisms of treatment resistance.

Adenoid cystic carcinoma↗

PubMed2006

LmrCD is a major multidrug resistance transporter in Lactococcus lactis.

When Lactococcus lactis is challenged with drugs it displays a multidrug resistance (MDR) phenotype. In silico analysis of the genome of L. lactis indicates the presence of at least 40 putative MDR transporters, of which only four, i.e. the ABC transporters LmrA, LmrC and LmrD, and the major facilitator LmrP, have been experimentally associated with the MDR. To understand the molecular basis of the MDR phenotype in L. lactis, we have performed a global transcriptome analysis comparing four independently isolated drug-resistant strains of L. lactis with the wild-type strain. The results show a strong and consistent upregulation of the lmrC and lmrD genes in all four strains, while the mRNA levels of other putative MDR transporters were not significantly altered. Deletion of lmrCD renders L. lactis sensitive to several toxic compounds, and this phenotype is associated with a reduced ability to secrete these compounds. Another gene, which is strongly upregulated in all mutant strains, specifies LmrR (YdaF), a local transcriptional repressor of lmrCD that belongs to the PadR family of transcriptional regulators and that binds to the promoter region of lmrCD. These results demonstrate that the heterodimeric MDR ABC transporter LmrCD is a major determinant of both acquired and intrinsic drug resistance of L. lactis.

ATP-Binding Cassette Transporters↗

PubMed2006

Microarray analysis of uterine epithelial gene expression during the implantation window in the mouse.

In mice, the uterus becomes transiently receptive to the hatched blastocyst on the day of implantation to allow its attachment to the luminal epithelium and subsequent invasion into the uterus. This uterine preparation for implantation is regulated by estradiol-17beta and progesterone, acting through their transcription factor receptors. Using ovariectomized mice treated with physiological regimens of these hormones, combined with methods to isolate RNA specifically from the uterine epithelium followed by transcriptome analysis on cDNA microarrays, 222 genes whose transcript abundance was specifically increased by estradiol-17beta and progesterone treatment were identified. Gene ontology analysis revealed an emphasis on genes involved with immune responses, extracellular matrix metabolism, and cell-to-cell communication. In situ hybridization to uterine sections isolated through the first 6 d of pregnancy identified novel sets of genes such as Bach, Myd88, Cd14, Isg20, and Lrp2 whose expression was restricted to the uterine epithelium during the implantation window. Particularly notable was the expression of the mRNA for members of the signaling pathway from the Toll-like receptors to its downstream targets such as Irg-1. The identification of these genes showing a cell type hormonally regulated pattern of expression in the uterus suggests novel functions for them during implantation.

Animals↗

PubMed2025

Evolutionary engineering and molecular characterization of an antimycin A-resistant Saccharomyces cerevisiae strain: the key role of pleiotropic drug resistance (PDR1).

Antimycin A, an antifungal agent that inhibits mitochondrial respiration, provides a useful model for studying resistance mechanisms. Antifungal resistance is an escalating clinical concern with limited treatment options available. To understand the molecular mechanisms of antimycin A resistance, a genetically stable, antimycin A-resistant Saccharomyces cerevisiae strain was successfully developed for the first time through an evolutionary engineering strategy, based on long-term systematic application of gradually increasing antimycin A stress in repetitive batch cultures without prior chemical mutagenesis. Comparative whole genome resequencing analysis of the evolved strain ant905-9 revealed two missense mutations in PDR1 and PRP8 genes involved in pleiotropic drug resistance and RNA splicing, respectively. Using CRISPR/Cas9 genome editing tools, the identified mutations were introduced individually and together into the reference strain, and it was confirmed that the Pdr1p.M732R mutation alone confers antimycin A-resistance in S. cerevisiae. Comparative transcriptomic analysis of the reverse-engineered Pdr1p.M732R strain showed alterations in PDR (pleiotropic drug resistance), transmembrane transport, vesicular trafficking, and autophagy pathways. Our results highlight the potential key role of PDR1 in antifungal drug resistance. This study provides new insights into mitochondrial drug resistance and the adaptive potential of yeast under respiratory stress.

Saccharomyces cerevisiae↗

PubMed2026

Third-generation whole-genome sequencing reveals the role of CNTNAP2 as a tumor suppressor gene in high-risk neuroblastomas.

BACKGROUND: Neuroblastoma is a common and aggressive pediatric sympathetic nervous system tumor. Genomic structural variants (SVs) contribute substantially to neuroblastoma, yet remain under-characterized in high-risk neuroblastomas. We aimed to elucidate neuroblastoma pathogenesis using third-generation whole-genome sequence high-risk cases to identify driver aberrations and explore potential therapeutic strategies. METHODS: We analyzed third-generation whole-genome sequencing data of 20 high-risk neuroblastoma samples and combined the findings with those obtained from the analysis of clinical samples, in vitro models, and public datasets. RESULTS: The contactin-associated protein-like 2 (CNTNAP2) gene was observed to be frequently aberrated because of structural variants in high-risk neuroblastoma samples. CNTNAP2 expression was significantly correlated with favorable histology and could be used to predict prognosis using clinical samples and neuroblastoma datasets. Overexpression and knockdown experiments and transcriptomic analysis revealed that CNTNAP2 was primarily involved in neuronal differentiation and axon guidance pathways; moreover, CNTNAP2 was required for neuroblastoma differentiation and affected cancer stemness. Immunoprecipitation and mass spectrometry revealed that CNTNAP2 interacted with cytoskeletal proteins like drebrin 1 (DBN1) and myosin-heavy chain 9 (MYH9). CNTNAP2 dynamically reorganises actin and microtubules for DBN1-mediated neuronal differentiation. CNTNAP2 also reduces CTNNB1 transcription and β-catenin pathway activation by inhibiting MYH9 nuclear translocation. CNTNAP2 overexpression in neuroblastoma cell lines resulted in cell cycle arrest, decreased cell proliferation and metastasis. CONCLUSIONS: The recurrent loss of CNTNAP2 in neuroblastoma contributes to an aggressive phenotype by impairing neuronal differentiation and increasing cancer stemness. These findings may serve as a foundation for developing therapeutic strategies to overcome barriers to differentiation.

Humans↗

PubMed2025

ves1α genes expression is the major determinant of Babesia bovis-infected erythrocytes cytoadhesion to endothelial cells.

Babesia bovis causes the most pathogenic form of babesiosis in cattle, resulting in high mortality in naive adults. This parasite invades red blood cells (RBCs) within the bovine hosts where they multiply and produce clinical disease. Babesia bovis exports numerous proteins into invaded RBCs changing its properties. Thus, the infected RBCs (iRBCs) are capable to cytoadhere in the microvasculature of internal organs and brain, leading to respiratory distress, neurologic signs, and mortality. Variant Erythrocyte Surface Antigen 1 (VESA1) is one of those exported proteins by B. bovis which represents a major virulence factor due to its central role in immune evasion by antigenic variation and intravascular parasite sequestration. VESA1 is a heterodimer protein encoded by ves1α and ves1β multigene family and localized on the ridges, the focal point for cytoadhesion. To gain further insights into the molecular mechanisms of cytoadhesion of B. bovis, we panned the parasites with bovine brain microvasculature endothelial cells, which resulted in obtaining several clones with different cytoadherence abilities. The transcriptome analysis of 2 high and 2 low cytoadherent clones revealed that ves1α sequences were diversified, likely resulting from genomic recombination. On the other hand, ves1β sequences were almost identical among these 4 clones. Insertion and expression of ves1α of a clone with high binding into ef-1α locus of a low binding clone increased cytoadherence confirming the role of ves1α suggested by our transcriptome data. Whole genome sequencing of cytoadherent clones revealed active locus of ves1 on chromosome 2. These results suggest that VESA1a proteins encoded by ves1α genes determine the cytoadherence strength of B. bovis and they are in the active site for recombination.

Animals↗

PubMed2005

Microarray analysis of Pseudomonas aeruginosa reveals induction of pyocin genes in response to hydrogen peroxide.

BACKGROUND: Pseudomonas aeruginosa, a pathogen infecting those with cystic fibrosis, encounters toxicity from phagocyte-derived reactive oxidants including hydrogen peroxide during active infection. P. aeruginosa responds with adaptive and protective strategies against these toxic species to effectively infect humans. Despite advances in our understanding of the responses to oxidative stress in many specific cases, the connectivity between targeted protective genes and the rest of cell metabolism remains obscure. RESULTS: Herein, we performed a genome-wide transcriptome analysis of the cellular responses to hydrogen peroxide in order to determine a more complete picture of how oxidative stress-induced genes are related and regulated. Our data reinforce the previous conclusion that DNA repair proteins and catalases may be among the most vital antioxidant defense systems of P. aeruginosa. Our results also suggest that sublethal oxidative damage reduces active and/or facilitated transport and that intracellular iron might be a key factor for a relationship between oxidative stress and iron regulation. Perhaps most intriguingly, we revealed that the transcription of all F-, R-, and S-type pyocins was upregulated by oxidative stress and at the same time, a cell immunity protein (pyocin S2 immunity protein) was downregulated, possibly leading to self-killing activity. CONCLUSION: This finding proposes that pyocin production might be another novel defensive scheme against oxidative attack by host cells.

DNA Repair↗

PubMed2005

Comparative analysis of transcriptional responses to saline stress in the laboratory and brewing strains of Saccharomyces cerevisiae with DNA microarray.

To construct yeast strains showing tolerance to high salt concentration stress, we analyzed the transcriptional response to high NaCl concentration stress in the yeast Saccharomyces cerevisiae using DNA microarray and compared between two yeast strains, a laboratory strain and a brewing one, which is known as a stress-tolerant strain. Gene expression dynamically changed following the addition of NaCl in both yeast strains, but the degree of change in the gene expression level in the laboratory strain was larger than that in the brewing strain. The response of gene expression to the low NaCl concentration stress was faster than that to the high NaCl concentration stress in both strains. Expressions of the genes encoding enzymes involved in carbohydrate metabolism and energy production in both strains or amino acid metabolism in the brewing strain were increased under high NaCl concentration conditions. Moreover, the genes encoding sodium ion efflux pump and copper metallothionein proteins were more highly expressed in the brewing strain than in the laboratory strain. According to the results of transcriptome analysis, candidate genes for the creation of stress-tolerant strain were selected, and the effect of overexpression of candidate genes on the tolerance to high NaCl concentration stress was evaluated. Overexpression of the GPD1 gene encoding glycerol-3-phosphate dehydrogenase, ENA1 encoding sodium ion efflux protein, and CUP1 encoding copper metallothionein conferred high salt stress tolerance to yeast cells, and our selection of candidate genes for the creation of stress-tolerant yeast strains based on the transcriptome data was validated.

Gene Expression Regulation, Fungal↗

PubMed2026

Comparative metabolomic and transcriptomic profiling of flavonoid diversity and antioxidant capacity in three Isatis species.

Flavonoids are key bioactive compounds in plants with significant health benefits. This study employs an integrated multi-omics approach to investigate flavonoid diversity and antioxidant capacity across three Isatis species: I. oblongata, I. tinctoria, and I. indigotica. Metabolomic profiling identified 200 flavonoids, with glycosides being the most abundant class. I. tinctoria exhibited the highest total flavonoid content and antioxidant activity, strongly correlated with the accumulation of 53 core differential flavonoid metabolites, most of which were glycosylated derivatives. Transcriptomic analysis revealed coordinated upregulation of phenylpropanoid pathway genes and specific UDP-glycosyltransferases (UGTs) in I. tinctoria, providing a genetic basis for its enhanced glycoside production. The study establishes a clear genotype-metabolite-phenotype linkage, highlighting glycosylation as a key mechanism underlying flavonoid-driven antioxidant superiority in Isatis. Although the current evidence is primarily correlative, the consistent and strong associations across independent transcriptomic, metabolomic, and antioxidant datasets provide a robust foundation for this conclusion. These findings offer new insights into the metabolic evolution and regulatory networks of flavonoids, with implications for breeding and metabolic engineering of high-value medicinal plants.

Flavonoids↗

PubMed2006

Catalog of gene expression in adult neural stem cells and their in vivo microenvironment.

Stem cells generally reside in a stem cell microenvironment, where cues for self-renewal and differentiation are present. However, the genetic program underlying stem cell proliferation and multipotency is poorly understood. Transcriptome analysis of stem cells and their in vivo microenvironment is one way of uncovering the unique stemness properties and provides a framework for the elucidation of stem cell function. Here, we characterize the gene expression profile of the in vivo neural stem cell microenvironment in the lateral ventricle wall of adult mouse brain and of in vitro proliferating neural stem cells. We have also analyzed an Lhx2-expressing hematopoietic-stem-cell-like cell line in order to define the transcriptome of a well-characterized and pure cell population with stem cell characteristics. We report the generation, assembly and annotation of 50,792 high-quality 5'-end expressed sequence tag sequences. We further describe a shared expression of 1065 transcripts by all three stem cell libraries and a large overlap with previously published gene expression signatures for neural stem/progenitor cells and other multipotent stem cells. The sequences and cDNA clones obtained within this framework provide a comprehensive resource for the analysis of genes in adult stem cells that can accelerate future stem cell research.

Animals↗

PubMed2005

Prolonged selection in aerobic, glucose-limited chemostat cultures of Saccharomyces cerevisiae causes a partial loss of glycolytic capacity.

Prolonged cultivation of Saccharomyces cerevisiae in aerobic, glucose-limited chemostat cultures (dilution rate, 0.10 h(-1)) resulted in a progressive decrease of the residual glucose concentration (from 20 to 8 mg l(-1) after 200 generations). This increase in the affinity for glucose was accompanied by a fivefold decrease of fermentative capacity, and changes in cellular morphology. These phenotypic changes were retained when single-cell isolates from prolonged cultures were used to inoculate fresh chemostat cultures, indicating that genetic changes were involved. Kinetic analysis of glucose transport in an 'evolved' strain revealed a decreased Km, while Vmax was slightly increased relative to the parental strain. Apparently, fermentative capacity in the evolved strain was not controlled by glucose uptake. Instead, enzyme assays in cell extracts of the evolved strain revealed strongly decreased capacities of enzymes in the lower part of glycolysis. This decrease was corroborated by genome-wide transcriptome analysis using DNA microarrays. In aerobic batch cultures on 20 g glucose l(-1), the specific growth rate of the evolved strain was lower than that of the parental strain (0.28 and 0.37 h(-1), respectively). Instead of the characteristic instantaneous production of ethanol that is observed when aerobic, glucose-limited cultures of wild-type S. cerevisiae are exposed to excess glucose, the evolved strain exhibited a delay of approximately 90 min before aerobic ethanol formation set in. This study demonstrates that the effects of selection in glucose-limited chemostat cultures extend beyond glucose-transport kinetics. Although extensive physiological analysis offered insight into the underlying cellular processes, the evolutionary 'driving force' for several of the observed changes remains to be elucidated.

Aerobiosis↗

PubMed2004

Genetic amplification of the transcriptional response to hypoxia as a novel means of identifying regulators of angiogenesis.

The cellular response to hypoxia involves the promotion of angiogenesis, leading to increased blood flow and oxygenation. The macrophage has been identified as an orchestrator of this response in several pathologies, through the release of angiogenic factors in response to hypoxia. We have produced the first comprehensive transcriptome analysis of hypoxic primary human macrophages with respect to the regulation of angiogenesis. There is a marked induction of genes encoding factors known to stimulate angiogenesis, rather than factors that inhibit this process. We show that overexpression of the transcription factor EPAS1 using a recombinant adenoviral vector amplifies the induction of genes encoding angiogenic proteins in response to hypoxia. This defines a new strategy for enhancing transcriptome and proteome analyses by overexpressing disease-implicated genes using viral gene transfer methodologies.

Adenoviridae↗