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PubMed2006

Isolation and expression profiling of genes upregulated in bone marrow-derived mononuclear cells of rheumatoid arthritis patients.

We have comprehensively identified the genes whose expressions are augmented in bone marrow-derived mononuclear cells (BMMC) from patients with Rheumatoid Arthritis (RA) as compared with BMMCs from Osteoarthritis (OA) patients, and named them AURA after augmented in RA. Both stepwise subtractive hybridization and microarray analyses were used to identify AURA genes, which were confirmed by northern blot analysis and/or reverse transcription polymerase chain reaction (RT-PCR). We also assessed their expression levels in individual patients by quantitative real-time RT-PCR. Of 103 AURA genes we have identified, the mRNA levels of the following 10 genes, which are somehow related to immune responses, were increased in many of the RA patients: AREG (=AURA9), FK506-binding protein 5 (FKBP5 = AURA45), C-type lectin superfamily member 9 (CLECSF9 = AURA24), tyrosylprotein sulfotransferase 1 (TPST1 = AURA52), lymphocyte G0/G1 switch gene (G0S2 = AURA8), chemokine receptor 4 (CXCR4 = AURA86), nuclear factor-kappa B (NF-kappaB = AURA25) and two genes of unknown function (FLJ11106 = AURA1, BC022398 = AURA2 and XM_058513 = AURA17). Since AREG was most significantly increased in many of the RA patients, we subjected it to further analysis and found that AREG-epidermal growth factor receptor signaling is highly activated in synovial cells isolated from RA patients, but not in OA synoviocytes. We propose that the expression profiling of these AURA genes may improve our understanding of the pathogenesis of RA.

Amphiregulin↗

PubMed2002

Expression profiling identifies strain-specific changes associated with ethanol withdrawal in mice.

Mice that exhibit characteristics of physical dependence following ethanol exposure serve as useful models of alcoholism in humans. The DBA/2J and C57BL/6J inbred strains differ in their behavioral response to ethanol withdrawal. Alterations in gene expression are believed to underlie neuroadaptation to ethanol dependence and tolerance. Therefore, the differences in ethanol withdrawal severity observed between the DBA/2J and C57BL/6J strains may be related to differential regulation of gene expression. We have used cDNA microarrays to determine the gene expression profile in the hippocampus of DBA/2J and C57BL/6J mice during withdrawal after chronic and acute ethanol exposure. Of the 7634 genes surveyed, approximately 2% were consistently differentially expressed by at least 1.4-fold in DBA/2J mice during chronic ethanol withdrawal. Less than 1% of the genes showed altered expression in C57BL/6J mice under the same conditions, or in DBA/2J mice during acute ethanol withdrawal. Strain- and treatment-specific patterns of altered expression were observed for multiple genes associated with the Janus kinase/signal transducers and activators of transcription and the mitogen activated protein kinase pathways. Genes associated with both pathways are regulated in DBA/2J mice during chronic ethanol withdrawal, and to a lesser extent during acute ethanol withdrawal. Only those genes associated with the mitogen-activated protein kinase (MAPK) pathway exhibited changes in expression in C57BL/6J mice during ethanol withdrawal. Furthermore, genes associated with retinoic acid-mediated signaling show differential expression exclusively in C57BL/6J mice. These findings represent significant differences in cellular adaptation to ethanol between the DBA/2J and C57BL/6J strains.

Animals↗

PubMed2002

Gene expression profiles in Ciona intestinalis cleavage-stage embryos.

A total of 1612 expression sequence tags derived from Ciona intestinalis cleavage-stage embryos were examined to explore detailed gene expression profiles. The 3' sequences indicate that the 1612 clones can be categorized into 1066 independent clusters. DDBJ database search suggested that 496 of them showed significant matches to reported proteins with distinct functions. Among them 69 are associated with cell-cell communications and 41 with transcription factors. In situ hybridization of all 1066 clusters showed that 84 clusters exhibited blastomere-specific pattern of expression, and many of these genes seem to encode for novel proteins. One of the interesting findings is that most of them were expressed in the precursor cells of multiple tissues. Among them 28 genes were expressed in the marginal zone of the 32-cell embryo. The blastomeres in this region are thought to receive an inductive signal from the vegetal blastomeres. Many of the blastomere-specific genes did not show similarity to known proteins. The present analysis therefore provides new information for further analyses on the cell fate specification in the Ciona embryo.

Animals↗

PubMed2004

Gene expression profiling identifies liver X receptor alpha as an estrogen-regulated gene in mouse adipose tissue.

Estrogens reduce adipose tissue mass in both humans and animals. The molecular mechanisms for this effect are, however, not well characterized. We took a gene expression profiling approach to study the direct effects of estrogen on mouse white adipose tissue (WAT). Female ovariectomized mice were treated for 10, 24 and 48 h with 17beta-estradiol or vehicle. RNA was extracted from gonadal fat and hybridized to Affymetrix MG-U74Av2 arrays. 17beta-Estradiol was shown to decrease mRNA expression of liver X receptor (LXR) alpha after 10 h of treatment compared with the vehicle control. The expression of several LXRalpha target genes, such as sterol regulatory element-binding protein 1c, apolipoprotein E, phospholipid transfer protein, ATP-binding cassette A1 and ATP-binding cassette G1, was similarly decreased. We furthermore identified a 1.5 kb LXRalpha promoter fragment that is negatively regulated by estrogen. Several genes involved in lipogenesis and lipolysis were identified as novel targets that could mediate estrogenic effects on adipose tissue. Finally, we show that ERalpha is the main estrogen receptor expressed in mouse white adipose tissue (WAT) with mRNA levels several hundred times higher than those of ERbeta mRNA.

Adipose Tissue↗

PubMed2006

Gene expression profiles in anatomically and functionally distinct regions of the normal aged human brain.

In this article, we have characterized and compared gene expression profiles from laser capture microdissected neurons in six functionally and anatomically distinct regions from clinically and histopathologically normal aged human brains. These regions, which are also known to be differentially vulnerable to the histopathological and metabolic features of Alzheimer's disease (AD), include the entorhinal cortex and hippocampus (limbic and paralimbic areas vulnerable to early neurofibrillary tangle pathology in AD), posterior cingulate cortex (a paralimbic area vulnerable to early metabolic abnormalities in AD), temporal and prefrontal cortex (unimodal and heteromodal sensory association areas vulnerable to early neuritic plaque pathology in AD), and primary visual cortex (a primary sensory area relatively spared in early AD). These neuronal profiles will provide valuable reference information for future studies of the brain, in normal aging, AD and other neurological and psychiatric disorders.

Aged↗

PubMed2004

Expression profiling reveals novel innate and inflammatory responses in the jejunal epithelial compartment during infection with Trichinella spiralis.

Infection with intestinal nematodes induces profound pathological changes to the gut that are associated with eventual parasite expulsion. We have applied expression profiling as an initial screening process with oligonucleotide microarrays (Affymetrix MG-U74AV2 gene chips) and time course kinetics to investigate gene transcription triggered by the intraepithelial nematode Trichinella spiralis in jejunal epithelium from BALB/c mice. Of the 4,114 genes detected, 2,617 were present in all uninfected and T. spiralis-infected replicates, 8% of which were notably upregulated, whereas 12% were downregulated at the time of worm expulsion (day 14 postinfection). Upregulation of goblet cell mucin gene transcripts intestinal mucin gene 3 (MUC3), calcium chloride channel 5 (CLCA5), and goblet cell gene 4 (GOB4) is consistent with enhanced production and alteration of mucus, whereas a 60- to 70-fold upregulation of transcripts for mast cell proteases 1 and 2 (MCPT-1 and -2) is consistent with intraepithelial mucosal mast cell recruitment. Importantly, there was novel expression of sialyltransferase 4C (SIAT4C), small proline-rich protein 2A (SPRR2A), and resistin-like molecule beta (RELMbeta) on day 14 postinfection. In contrast, DNase I and regenerating protein 3 (REG3) transcripts were substantially downregulated. Time course analyses revealed early (within 48 h of infection) induction of Siat4c, Sprr2A, and Relmbeta and later (within 120 h) induction of Mcpt-1 and -2. The findings demonstrate early innate responses and later inflammatory changes within the epithelium. The early epithelial responses may be associated both with repair (Sprr2A) and with the development of innate immunity (Siat4c and Relmbeta).

Animals↗

PubMed2003

MLL-mediated transcriptional gene regulation investigated by gene expression profiling.

The human mixed lineage leukemia (MLL) gene is involved in about 50 different chromosomal translocations, associated with the disease phenotype of acute leukemia. However, the normal function of MLL is less understood. Homozygous knockouts of murine Mll were embryonal lethal, while heterozygous disruption led to aberrant hox gene expression associated with skeletal malformations, growth retardation, and impaired hematopoiesis. To understand MLL functions on the molecular level, gene expression profiling experiments were performed with a pair of murine cell lines (MLL(+/+) and MLL(-/-)). Microarray hybridization experiments revealed 197 potential target genes that are differentially expressed, providing new and important clues about MLL functions.

Animals↗

PubMed2001

Statistical pattern analysis of gene expression profiles for glioblastoma tissues and cell lines.

The recent development and refinement of cDNA array and genechip techniques allows for large-scale parallel screening of gene expression and thereby provides a global assessment of molecular events transpiring in cell populations. We hypothesized that such an approach might help illuminate current issues in glioma research. To what degree are glioblastoma multiforme (GBM) cell lines representative of primary GBM tumors? We carried out a gene expression profiling study using cDNA array technology on 10 GBM primary tissues and 3 GBM cell lines. The gene expression levels were quantified, and the within-subject ranks of the gene expression levels were subsequently evaluated by hierarchical clustering analysis, multidimensional scaling analysis, and principal component analysis. Hierarchical cluster analysis shows that the 3 cell lines form one main cluster and the 10 tissue samples form a separate cluster. Multidimensional scaling and principal components analysis provided further graphical demonstration that the cell lines are clearly different from the tissue samples and that the cell lines are more different between themselves than are the tissues.

Central Nervous System Neoplasms↗

PubMed2006

Gene expression profiling reveals the profound upregulation of hypoxia-responsive genes in primary human astrocytes.

Oxygen is vital for the development and survival of mammals. In response to hypoxia, the brain initiates numerous adaptive responses at the organ level as well as at the molecular and cellular levels, including the alteration of gene expression. Astrocytes play critical roles in the proper functioning of the brain; thus the manner in which astrocytes respond to hypoxia is likely important in determining the outcome of brain hypoxia. Here, we used microarray gene expression profiling and data-analysis algorithms to identify and analyze hypoxia-responsive genes in primary human astrocytes. We also compared gene expression patterns in astrocytes with those in human HeLa cells and pulmonary artery endothelial cells (ECs). Remarkably, in astrocytes, five times as many genes were induced as suppressed, whereas in HeLa and pulmonary ECs, as many as or more genes were suppressed than induced. More genes encoding hypoxia-inducible functions, such as glycolytic enzymes and angiogenic growth factors, were strongly induced in astrocytes compared with HeLa cells. Furthermore, gene ontology and computational algorithms revealed that many target genes of the EGF and insulin signaling pathways and the transcriptional regulators Myc, Jun, and p53 were selectively altered by hypoxia in astrocytes. Indeed, Western blot analysis confirmed that two major signal transducers mediating insulin and EGF action, Akt and MEK1/2, were activated by hypoxia in astrocytes. These results provide a global view of the signaling and regulatory network mediating oxygen regulation in human astrocytes.

Algorithms↗

PubMed2002

Modulation of polyglutamine-induced cell death by genes identified by expression profiling.

The majority of triplet-repeat diseases are caused by mutated genes with an extended polyglutamine tract, exemplified by Huntington's disease (HD). In order to model HD pathogenesis in a controlled system, we developed stable PC12 cell lines that express exon 1 fragments of the huntingtin gene with 23 or 74 polyglutamines driven by an inducible doxycycline (dox)-sensitive promoter (HD-23Q or HD-74Q). We aimed to identify early perturbations induced by the mutation by studying expression levels of 1824 genes at 0, 5, 10 and 18 hours after induction, using adaptor-tagged competitive PCR (ATAC-PCR). At these time points, the cells show no appreciable death or mitochondrial impairment and very low inclusion levels. A total of 126 genes, including 69 known genes, exhibited statistically significant alterations in the HD-74Q cell lines but no changes in the HD-23Q lines. We tested 11 of these genes for their abilities to modulate polyglutamine-induced cell death in transiently transfected cell models. Five genes [glucose transporter 1 (Glut1), phosphofructokinase muscle isozyme (Pfkm), prostate glutathione-S -transferase 2 (Gstm2), RNA-binding motif protein 3 (Rbm3) and KRAB-A interacting protein 1 (Krip-1)] significantly suppressed cell death in both neuronal precursor and non-neuronal cell lines, suggesting that these transcriptional changes were relevant to polyglutamine pathology. The efficient recovery of functionally relevant genes supports the utility of gene expression profiling for discovering pathways related to pathogenesis, and the importance of analyzing molecular events in the early stages of disease.

Animals↗

PubMed2002

Gene expression profile of Vitamin D3 treated HL60 cells shows an incomplete molecular phenotypic conversion to monocytes.

By high density oligonucleotide microarrays we have studied the expression profile of proliferating and VD treated HL60 cells and the molecular phenotype of VD monocytes and that of CD14+ peripheral monocytes has been compared. The results indicate that important changes in functional categories of the differentially expressed genes underlie the differentiation transition from myeloblasts to monocytes. This differential gene expression pattern leads to an increased expression of mRNAs involved in surface and external activities since many of the VD induced genes belong to ligand binding, receptors, cell surface antigens, defense/immunity and adhesion molecules functional categories. The results also indicate that the molecular phenotypes of monocytes and VD induced cells diverge for a small but significant set of defense related genes. Particularly, class II MHC genes are not expressed in these cells. Furthermore, the high levels of expression of these genes induced by serum treatment of monocytes are decreased by VD.

Cell Differentiation↗

PubMed2004

Global gene expression profiling of human endometrial receptivity.

Scientific knowledge on the molecular changes that occur during the window of implantation is fundamental for the understanding of human reproduction. To gain a global molecular understanding of human endometrial receptivity, we have compared gene expression profiles of pre-receptive (day LH + 2) versus receptive (LH + 7) in well characterized human endometrial biopsies. The samples were analyzed using the Affymetrix HG-95A array, a high density oligonucleotide microarray comprising more than 12,000 genes. In this work, we present part of our results and a comparison with similar works published in the literature. Identified genes include not only genes previously documented to be involved in implantation but also genes for which a role in endometrial receptivity, or even endometrial expression, has not been previously described. Collectively, these studies identify new candidate markers that may be used to diagnose unequivocally the receptive endometrium.

Endometrium↗

PubMed2006

Gene expression profiles of erythroid precursors characterise several mechanisms of the action of hydroxycarbamide in sickle cell anaemia.

Hydroxycarbamide (HC) (or hydroxyurea) has been reported to increase fetal haemoglobin levels and improve clinical symptoms in sickle cell anaemia (SCA) patients. However, the complete pathway by which HC acts remains unclear. To study the mechanisms involved in the action of HC, global gene expression profiles were obtained from the bone marrow cells of a SCA patient before and after HC treatment using serial analysis of gene expression. In the comparison of both profiles, 147 differentially expressed transcripts were identified. The functional classification of these transcripts revealed a group of gene categories associated with transcriptional and translational regulation, e.g. EGR-1, CENTB1, ARHGAP4 and RIN3, suggesting a possible role for these pathways in the improvement of clinical symptoms of SCA patients. The genes involved in these mechanisms may represent potential tools for the identification of new targets for SCA therapy.

Adult↗

PubMed2004

Differential gene expression profiles of radioresistant oesophageal cancer cell lines established by continuous fractionated irradiation.

Radiation therapy is a powerful tool for the treatment of oesophageal cancer. We established radioresistant cell lines by applying fractionated irradiation in order to identify differentially expressed genes between parent and radioresistant cells. Six oesophageal cancer cell lines (TE-2, TE-5, TE-9, TE-13, KYSE170, and KYSE180) were treated with continuous 2 Gy fractionated irradiation (total dose 60 Gy). We compared expression profiles of each parent and radioresistant lines on a cDNA microarray consisting of 21168 genes. In the fractionated irradiation trial, four radioresistant sublines (TE-2R, TE-9R, TE-13R, KYSE170R) were established successfully, and we identified 19 upregulated and 28 downregulated genes common to radioresistant sublines. Upregulated genes were associated with apoptosis and inflammatory response (BIRC2 and COX-2), DNA metabolism (CD73), and cell growth (PLAU). Downregulated genes were associated with apoptosis (CASP6), cell adhesion (CDH1 and CDH3), transcription (MLL3), and cell cycle (CDK6). Some of these genes were known to be associated with radiation response, such as COX-2, but others were novel. Reverse transcription-polymerase chain reaction confirmed that genes selected by cDNA microarray were overexpressed in clinical specimens of radioresistant cases. Global gene analysis of radioresistant sublines may provide new insight into mechanisms of radioresistance and effective radiation therapy.

Biomarkers, Tumor↗

PubMed2004

Differences in gene expression profiles of diabetic and nondiabetic patients undergoing cardiopulmonary bypass and cardioplegic arrest.

BACKGROUND: Diabetes mellitus is an independent risk factor for early postoperative mortality and complications after coronary artery bypass grafting (CABG). We sought to compare the cardiac gene expression responses to cardiopulmonary bypass (CPB) and cardioplegic arrest (C) in patients with and without diabetes. METHODS AND RESULTS: Twenty atrial myocardium samples were harvested from 5 type II insulin-dependent diabetic and 5 matched nondiabetic patients undergoing CABG, before and after CPB/C. Oligonucleotide microarray analyses of 12625 genes were performed on the 10 sample pairs using matched pre-CPB tissues as controls. Array results were validated with Northern blotting and immunoblotting. Compared with pre-CPB/C, post-CPB/C myocardial tissues revealed 851 upregulated and 480 downregulated genes with a threshold P< or =0.025 (signal-to-noise ratio, 4.04) in the diabetic group, compared with 480 upregulated and 626 downregulated genes (signal-to-noise ratio, 3.04) in the nondiabetic group (P<0.001). There were 18 genes that were upregulated >4-fold in diabetic and nondiabetic patients (including inflammatory/transcription activators FOS, CYR 61, and IL-6, apoptotic gene NR4A1, stress gene DUSP1, and glucose-transporter gene SLC2A3). However, 28 genes showed such marked upregulation in the diabetic group exclusively (including inflammatory/transcription activators MYC, IL8, IL-1beta, growth factor vascular endothelial growth factor, amphiregulin, and glucose metabolism-involved gene insulin receptor substrate 1), and 27 genes in the nondiabetic group only, including glycogen-binding subunit PPP1R3C. CONCLUSIONS: Gene expression profile after CPB/C is quantitatively and qualitatively different in patients with diabetes. These results have important implications for the design of tailored myocardial protection and operative strategies for diabetic patients undergoing CPB/C.

Actins↗

PubMed2005

Differential gene expression profile reveals deregulation of pregnancy specific beta1 glycoprotein 9 early during colorectal carcinogenesis.

BACKGROUND: APC (Adenomatous polyposis coli) plays an important role in the pathogenesis of both familial and sporadic colorectal cancer. Patients carrying germline APC mutations develop multiple colonic adenomas at younger age and higher frequency than non-carrier cases which indicates that silencing of one APC allele may be sufficient to initiate the transformation process. METHODS: To elucidate the biological dysregulation underlying adenoma formation we examined global gene expression profiles of adenomas and corresponding normal mucosa from an FAP patient. Differential expression of the most significant gene identified in this study was further validated by mRNA in situ hybridization, reverse transcriptase PCR and Northern blotting in different sets of adenomas, tumours and cancer cell lines. RESULTS: Eighty four genes were differentially expressed between all adenomas and corresponding normal mucosa, while only seven genes showed differential expression within the adenomas. The first group included pregnancy specific beta-1 glycoprotein 9 (PSG9) (p < 0.006). PSG9 is a member of the carcinoembryonic antigen (CEA)/PSG family and is produced at high levels during pregnancy, mainly by syncytiotrophoblasts. Further analysis of sporadic and familial colorectal cancer confirmed that PSG9 is ectopically upregulated in vivo by cancer cells. In total, deregulation of PSG9 mRNA was detected in 78% (14/18) of FAP adenomas and 75% (45/60) of sporadic colorectal cancer cases tested. CONCLUSION: Detection of PSG9 expression in adenomas, and at higher levels in FAP cases, indicates that germline APC mutations and defects in Wnt signalling modulate PSG9 expression. Since PSG9 is not found in the non-pregnant adult except in association with cancer, and it appears to be an early molecular event associated with colorectal cancer monitoring of its expression may be useful as a biomarker for the early detection of this disease.

Adenomatous Polyposis Coli↗

PubMed2005

Genome-wide expression profiling in malaria infection reveals transcriptional changes associated with lethal and nonlethal outcomes.

High-density oligonucleotide microarrays are widely used to study gene expression in cells exposed to a variety of pathogens. This study addressed the global genome-wide transcriptional activation of genes in hosts infected in vivo, which result in radically different clinical outcomes. We present an analysis of the gene expression profiles that identified a set of host biomarkers which distinguish between lethal and nonlethal blood stage Plasmodium yoelii malaria infections. Multiple biological replicates sampled during the course of infection were used to establish statistically valid sets of differentially expressed genes. These genes that correlated with the intensity of infection were used to identify pathways of cellular processes related to metabolic perturbations, erythropoiesis, and B-cell immune responses and other innate and cellular immune responses. The transcriptional apparatus that controls gene expression in erythropoiesis was also differentially expressed and regulated the expression of target genes involved in the host's response to malaria anemia. The biological systems approach provides unprecedented opportunities to explore the pathophysiology of host-pathogen interactions in experimental malaria infection and to decipher functionally complex networks of gene and protein interactions.

Animals↗

PubMed2004

Expression profiling in spinal muscular atrophy reveals an RNA binding protein deficit.

Spinal muscular atrophy is a common neuromuscular disorder caused by deletions or mutations within the survival motor neuron gene. The reason for specific motor neuron loss within the disease is still unclear. Expression profiling has been carried out in two models of spinal muscular atrophy; the heterozygote mouse model and human primary muscle cultures from a spinal muscular atrophy patient. A group of RNA binding proteins are up-regulated in spinal muscular atrophy motor neurons. One such protein, BRUNOL3, is highly expressed within spinal cord and muscle and also at the same developmental stage as survival motor neuron. The differential expression of Brunol3 has been confirmed with real-time RT-PCR in spinal cord and muscle of three different models of spinal muscular atrophy. BRUNOL3 has been shown to co-localise with survival motor neuron in the nuclei of neuronal cells and to co-immunoprecipitate with Smn in mouse brain. This is the first time that a link has been established between RNA binding proteins and survival motor neuron within motor neurons.

Adolescent↗