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At least 991 records · Page 55Linked to original sources
PubMed2005

Wound site neutrophil transcriptome in response to psychological stress in young men.

Communication between the central nervous and the immune system occurs through chemical messengers secreted by nerve cells, endocrine organs, or immune cells. Psychological stressors can disrupt these networks. We have previously observed that disruption of the neuroendocrine immune system adversely influences a broad range of physiological processes including wound healing. Migration of neutrophils to the wound site is an early event that induces a transcriptional activation program, which regulates cellular fate and function, and promotes wound healing. In this study, we have sought to identify stress-sensitive transcripts in wound site neutrophils. A skin blister model was used to collect wound fluid and wound site neutrophils from four young men, experiencing or not examination stress. Self-reported stress was recorded using the Beck Depression Inventory. Stress decreased growth hormone levels at the wound site and was related to impaired wound healing in all subjects. High density microarray analyses were performed using RNA from wound site neutrophils. Results show that psychological stress had an overall suppressive effect on the neutrophil transcriptome. Of the 22,283 transcripts screened, 0.5% were downregulated whereas only under 0.3% were induced by stress in all four out of four subjects. Functionally, stress tilted the genomic balance towards genes encoding proteins responsible for cell cycle arrest, death, and inflammation. Further effort to gain a more comprehensive understanding of the functional significance of such behavior-genome interaction is warranted.

Adult↗
PubMed2007

Distinct and shared transcriptomes are regulated by microphthalmia-associated transcription factor isoforms in mast cells.

The Microphthalmia-associated transcription factor (Mitf) is an essential basic helix-loop-helix leucine zipper transcription factor for mast cell development. Mice deficient in Mitf harbor a severe mast cell deficiency, and Mitf-mutant mast cells cultured ex vivo display a number of functional defects. Therefore, an understanding of the genetic program regulated by Mitf may provide important insights into mast cell differentiation. Multiple, distinct isoforms of Mitf have been identified in a variety of cell types; we found that Mitf-a, Mitf-e, and Mitf-mc were the major isoforms expressed in mast cells. To determine the physiologic function of Mitf in mast cells, we restored expression of these isoforms in primary mast cells from Mitf(-/-) mice. We found that these isoforms restored granular morphology and integrin-mediated migration. By microarray analysis, proteases, signaling molecules, cell surface receptor, and transporters comprised the largest groups of genes up-regulated by all isoforms. Furthermore, we found that isoforms also regulated distinct genes sets, suggesting separable biological activities. This work defines the transcriptome regulated by Mitf in mast cells and supports its role as master regulator of mast cell differentiation. Expression of multiple isoforms of this transcription factor may provide for redundancy of biological activities while also allowing diversity of function.

Animals↗
PubMed2006

Alternative splicing increases complexity of stem cell transcriptome.

Development of highly anticipated stem cell-based therapies requires a detailed understanding of mechanisms regulating biological properties of these cells. Comprehensive identification of all biological molecules produced in stem cells is an important step toward this goal. During the past several years, microarray studies have essentially identified genes that are transcriptionally activated in various embryonic and adult stem cell populations. However, the extent of post-transcriptional modifications within the stem cell transcriptome remained undetermined. Recently, we presented evidence that thousands of genes expressed in hematopoietic and embryonic stem cells undergo alternative splicing. Using combined computational and experimental analyses, we found that the frequency of alternative splicing is especially high in tissue-specific genes, as compared to ubiquitous genes. Our results also indicate that negative regulation of constitutively active splicing sites can be a prevalent mode for generation of splicing variants, and that alternative splicing is generally not conserved between orthologous genes in human and mouse. Here, we discuss the implications of our findings for stem cell biology, and present possible approaches toward genome-wide identification and characterization of splice variants.

Alternative Splicing↗
PubMed2003

Genomics, transcriptomics, proteomics, and numbers.

OBJECTIVE: To review the advances in clinically useful molecular biologic techniques and to identify their applications in clinical practice, as presented at the 11th Annual William Beaumont Hospital DNA Symposium. DATA SOURCES: The 8 manuscripts submitted were reviewed, and their major findings were compared with literature on the same or related topics. STUDY SELECTION: Manuscripts address the use of molecular techniques in microbiology to evaluate infectious disease and epidemiology; molecular microbiology methods, including rapid-cycle real-time polymerase chain reaction; peroxisome proliferator-activated receptor gamma as a potential therapeutic target in inflammatory bowel disease or colon cancer; the effect of nonapoptotic doses of the bisbenizamide dye Hoechst 33342 on luciferase expression in plasmid-transfected BC3H-1 myocytes; the routine use of cystic fibrosis screening and its challenges; and the use of flow cytometry and/or chromosomal translocation in the diagnostic evaluation of hematopoietic malignancies. DATA SYNTHESIS: Three current issues related to the use of molecular tests in clinical laboratories are (1) the restriction on introducing new tests secondary to existing patents or licenses; (2) the preanalytic variables for the different specimen types currently in use, including whole blood, plasma, serum, fresh or frozen tissues, and free-circulating DNA; and (3) the interpretation of studies evaluating the association of complex diseases with a single mutation or single-nucleotide polymorphism. Molecular methods have had a major impact on infectious disease through the rapid identification of organisms, the evaluation of outbreaks, and the characterization of drug resistance when compared with standard culture techniques. The activation of peroxisome proliferator-activated receptor gamma stimulated by thiazolidinedione is useful in the treatment of type II diabetes mellitus and may have value in preventing inflammatory bowel disease or colon cancer. Hoechst 33342 binding to adenine-thymine-rich regions in the minor groove of DNA is a fluorescent stain for DNA and initiates apoptosis at >10 microg/mL. Lower doses of Hoechst 33342 promote luciferase expression by a mechanism that may involve binding to cryptic promoters facilitated by dye-associated misalignment of the tertiary structure of DNA. The routine use of cystic fibrosis screening is complicated by the more than 1000 mutations associated with the disease. The use of 4-color flow cytometry and the detection of chromosomal translocation are both invaluable aids in establishing the diagnosis of lymphoid or myeloid hematopoietic malignancies. CONCLUSIONS: The current postgenomic era will continue to emphasize the use of microarrays and database software for genomic, transcriptomic, and proteomic screening in the search for useful clinical assays. The number of molecular pathologic techniques will expand as additional disease-associated mutations are defined.

Cystic Fibrosis↗
PubMed2002

Transcriptomics in predictive toxicology.

Once again, genomics is about to change drug development. Following its major impact on target discovery and assay development, which increased the number of compounds at early stages of the process, genomics is now zeroing in on the prediction of potential toxicological problems of compounds. Toxicogenomics is the analysis of toxicological processes at the transcriptome level of a target organ or cell. By simultaneously monitoring the effect of a compound on the transcription levels of hundreds to thousands of genes, toxicogenomics can provide an enormous amount of data. This data bears information on the way in which compounds act at the molecular level, reaching far beyond the mere conclusion of whether or not a particular toxicological outcome is elicited. By compiling transcription profiles for well-known toxicants, we are beginning to learn how to analyze this novel type of data in the context of mechanistic and predictive toxicology.

Animals↗
PubMed2003

Aging-associated changes in cardiac gene expression: large scale transcriptome analysis.

Aging and aging-related diseases are associated with altered patterns of gene expression, involving quantitative and qualitative changes in the abundance of specific transcripts. A complete and simultaneous analysis of gene expression should therefore lead to important insights into the transcriptional mechanisms underlying the aging process. Recently, we have employed high-throughput gene expression profiling to study transcriptional activity in heart. Two technologies, serial analysis of gene expression (SAGE) and gene expression arrays, allow rapid, large-scale expression profiling, which provides information about the dynamics of total gene expression with age and which can be employed to identify candidate genes that may serve as diagnostic and prognostic markers in age-associated cardiac diseases. The accompanying gene predictions from high-throughput gene expression profiling provide a starting point for understanding the function, the complexity of interactions, and the role of genes in promoting cellular/organismal phenotypes during senescence and disease. In this review we describe the current state of transcriptome profiling by SAGE and microarrays and discuss how results generated with these approaches in heart can be applied to the study of aging and the treatment of cardiovascular diseases.

Aging↗
PubMed2003

Complex analysis of genes involved in the inflammatory response: interleukin-1-induced differential transcriptome of cultured human hepatoma HepG2 cells.

The systemic inflammatory reaction (acute phase response) is induced by many noxious stimuli but in all cases the inflammatory cytokines, such as interleukin-1-beta (IL-1beta) and interleukin-6 (IL-6), are involved. Liver cell response to inflammation manifested by a characteristic change in the profile of synthesized plasma proteins (acute phase proteins) has been extensively studied. Here we describe a model system of cultured human hepatoma HepG2 cells stimulated with IL-1beta to evaluate the transcriptome induced by this cytokine during 24 h of treatment. By using differential display analysis we found IL-1beta-induced upregulation of several genes coding for cellular trafficking/motor proteins, proteins participating in the translation machinery or involved in posttranscription/posttranslation modifications, proteases, proteins involved in cellular metabolism, activity modulators, proteins of the cell cycle machinery and also some new proteins so far functionally not classified.

Carcinoma, Hepatocellular↗
PubMed2004

Transcriptome analysis of endometrial cancer identifies peroxisome proliferator-activated receptors as potential therapeutic targets.

Endometrial cancer is the most common gynecologic malignancy, frequently arising in association with obesity and diabetes mellitus. To identify gene pathways contributing to endometrial cancer development, we studied the transcriptome of 20 endometrial cancers and 11 benign endometrial tissues using cDNA microarrays. Among the transcript changes identified in endometrial cancer were up-regulation of the nuclear hormone receptors peroxisome proliferator-activated receptors (PPAR) alpha and gamma, whereas retinoid X receptor beta was down-regulated. To clarify the contribution of PPARalpha to endometrial carcinogenesis, we did experiments on cultured endometrial carcinoma cells expressing this transcript. Treatment with fenofibrate, an activating ligand for PPARalpha, significantly reduced proliferation and increased cell death, suggesting that altered expression of nuclear hormone receptors involved with fatty acid metabolism leads to deregulated cellular proliferation and apoptosis. These results support further investigation of members of the PPAR/retinoid X receptor pathway as novel therapeutic targets in endometrial cancer.

Cell Death↗
PubMed2004

[Transcriptome profiling of marrow mononuclear cells of patients with myelodysplastic syndrome using cDNA microarray analysis].

OBJECTIVE: To study the gene expression profiles of patients with myelodysplastic syndrome (MDS) and try to identify some genes with pathogenetic and diagnostic relevance. METHODS: The bone marrow mononuclear cells (BMMNCs) of 10 patients with MDS, including 4 cases of refractory anemia (RA), 1 case of refractory thrombocytopenia (RTC), 4 cases of RA with excess blasts (RAEB), and 1 case of RAEB in transformation (RAEBt), were isolated and the total RNA was extracted and underwent transcriptome analysis by using customized cDNA microarray with 500 gene clones. Seventeen specimens of normal bone marrow, as controls, were collected from the ribs of 17 patients with chest tumors. Cluster software was used to make analysis. Semiquantitative RT-PCR was carried out to confirm the results of microarray analysis. RESULTS: 95 genes, such as the genes of thrombospondin 1 (THBS1), phosphatase and tensin homolog (PTEN), MAX dimerization protein (MAD), DNA-damage-inducible transcript 3 (DDIT3), ets variant gene 1 (ETV1), G1 to S phase transition 1 (GSPT1), were shown to be abnormally expressed in at least 5 MDS patients compared to the normal controls, involving cell growth and differentiation regulation, cell cycle control, signaling, and redox. The 10 MDS patients in different stages were clustered into two distinct groups, whereas a case with refractory thrombocytopenia and other RA patients were clustered into two subgroups. Semiquantitative RT-PCR revealed the identical results in 3 (60%) of the 5 genes determined by microarray analysis. Further analysis on samples from 50 MDS patients confirmed the different expression levels of RNA helicase-related protein (RNAHP), GSPT1, and DDIT3 between the MDS patients and the normal controls. CONCLUSION: The technology of microarray can reveal the intrinsic molecular features of MDS patients and the detection of DDIT3 and RNAHP expression may be useful for the diagnosis of MDS.

Adult↗
PubMedDate not supplied

Transcriptomic characterization of four classes of cell-cell/cell-matrix genes in brains and hearts of wild type and connexin43 null mice.

We have used a highly quantifiable cDNA microarray method to determine the stabilities and expression levels within gene families involved in cell-cell and cell-matrix interactions in neonatal mouse brain and heart. In addition, we have characterized the extent to which deletion of the gap junction protein connexin43 (Cx43) affects these characteristics. Our observations for individual genes revealed a range of differences and variabilities in transcription level among family members; calculation of the genomic patholog (a global measure of gene expression alteration) indicates that these cell interaction genes contribute disproportionately to the overall phenotype. We found significant transcriptomic differences between brain and heart, that deletion of Cx43 considerably decreased gene expression variability and that the average contribution to the pathology of the genes whose encoded proteins are involved in cell-cell or cell-matrix interaction in the Cx43-null mice was about twenty times higher than that of other genes. These findings indicate that gap junction gene expression influences the expression of other genes involved in intercellular and cell-substrate interaction and that expression of these genes is under strong regulatory pressure in the Cx43-null mouse, presumably representing a compensatory response to Cx43 deletion.

Animals↗
PubMed2005

The cell wall of Paracoccidioides brasiliensis: insights from its transcriptome.

The cell wall of a human pathogenic fungus is in contact with the host, serves as a barrier against host defense mechanisms and harbors most fungal antigens. In addition, cell wall biosynthesis pathways have been recognized as essential to viability and as specific drug targets. Paracoccidioides brasiliensis is a dimorphic fungus that presents mycelium morphology in the free environment and causes infection in a yeast form. The morphogenetic conversion is correlated with changes in the cell wall composition, organization and structure. Based on transcriptome analysis, the enzymes involved in the biosynthesis and remodeling of cell wall polysaccharides, as well as several cell wall-associated molecules of P. brasiliensis, were identified and addressed in further detail.

Cell Wall↗
PubMed2005

Molecular chaperones in the Paracoccidioides brasiliensis transcriptome.

Paracoccidioides brasiliensis is a thermally dimorphic and a human pathogenic fungus. Our group has partially sequenced its transcriptome and generated a database of mycelial and yeast PbAESTs (P. brasiliensis assembled expressed sequence tags). In the present review we describe the identification of PbAESTs encoding molecular chaperones. These proteins, involved in protein folding and renaturation, are also implicated in several other biological processes, where the dimorphic transition is of particular interest. Another important issue concerning these proteins refers to their participation in the immunopathogenicity of infectious diseases. We have found 438 ESTs (184 in mycelium and 253 in yeast) encoding P. brasiliensis molecular chaperones and their co-chaperones, which were clustered in 48 genes. These genes were classified in families, corresponding to three small chaperones, nine HSP40s, 10 HSP60s, seven HSP70s, five HSP90s, four HSP100s, and 10 other chaperones. These results greatly increase the knowledge on P. brasiliensis molecular chaperones, since only eight of such proteins had been previously characterized.

DNA, Complementary↗
PubMed2005

Transcriptome overview of Paracoccidioides brasiliensis proteases.

Proteases perform a wide variety of functions inside and outside cells, regulating many biological processes. Infectious microorganisms use proteases, either secreted or attached to their cell surface to weaken and invade their hosts. Therefore, proteases are targets for drugs against a diverse set of diseases. Paracoccidioides brasiliensis is the most prevalent fungal pathogen causing systemic mycosis in Latin America. The development of paracoccidioidomycosis depends on interactions between fungal and host components and proteases have been described as important factors implicated in the mechanism of host colonization by fungi. The primary goal for this study is to present an overview of the transcriptome sequences--identified cDNAs that encode proteases. We obtained a total of 53 cDNAs encoding proteases; 15 were classified as ATP-independent, 12 as ATP-dependent, 22 as proteasome subunits, and 4 as deubiquitinating proteases. The mechanisms and biological activity of these proteases differ in substrate specificity and in catalytic mechanisms.

Base Sequence↗
PubMed2005

Transporters in the Paracoccidioides brasiliensis transcriptome: insights on drug resistance.

In the struggle for life, the capacity of microorganisms to synthesize and secrete toxic compounds (inhibiting competitors) plays an important role in successful survival of these species. This ability must come together with the capability of being unaffected by these same compounds. Several mechanisms are thought to avoid the toxic effects. One of them is toxin extrusion from the intracellular environment to the outside vicinity, using special transmembrane proteins, referred to as transporters. These proteins are also important for other reasons, since most of them are involved in nutrient uptake and cellular excretion. In cancer cells and in pathogens, and particularly in fungi, some of these proteins have been pointed out as responsible for an important phenotype known as multidrug resistance (MDR). In the present study, we tried to identify in the Paracoccidioides brasiliensis transcriptome, transporter-ortholog genes from the two major classes: ATP binding cassette and major facilitator superfamily transporter. We found 22 groups with good similarity with other fungal ATP binding cassette transporters, and four Paracoccidioides brasilienses assembled expressed sequence tags that probably code for major facilitator superfamily proteins. We also focused on fungicide resistance orthologs already characterized in other pathogenic fungi. We were able to find homologs to C. albicans CDR1, CDR2, and MDR1, Saccharomyces cerevisiae PDR5 and Aspergillus AtrF genes, all of them related to azole resistance. As current treatment for paracoccidioidomycosis mainly uses azole derivatives, the presence of these genes can be postulated to play a similar role in P. brasiliensis, warning us for the possibility of resistant isolate emergence.

ATP-Binding Cassette Transporters↗
PubMed2005

Therapeutic targets in Paracoccidioides brasiliensis: post-transcriptome perspectives.

The rise in antifungal resistance, observed as a result of the increasing numbers of immunocompromised patients, has made the discovery of new targets for drug therapy imperative. The description of the Paracoccidioides brasiliensis transcriptome has allowed us to find alternatives to refine current therapy against paracoccidioidomycosis. We used comparative analysis of expressed sequence tags to find promising drug targets that have been addressed in other pathogens. We divided the analysis into six different categories, based on the involvement of the targeted mechanisms in the cell: i) cell wall construction, ii) plasma membrane composition, iii) cellular machinery, iv) cellular metabolism, v) signaling pathways, and vi) other essential processes. Through this approach, it has been possible to infer strategies to develop alternative drugs against this pathogen.

Antifungal Agents↗
PubMed2006

Microarray-mediated transcriptome analysis of the tributyltin (TBT)-resistant bacterium Pseudomonas aeruginosa 25W in the presence of TBT.

The tributyltin (TBT)-resistant bacterium, Pseudomonas aeruginosa 25W, which was isolated in seawater from the Arabian Sea, was subjected to transcriptome analysis in the presence of high concentrations of TBT. Only slight effects were observed at TBT concentration of 50 microM, but exposure to 500 microM resulted in the upregulation of 6 genes and the downregulation of 75. Among the 75 downregulated genes, 53% (40 out of 75) were of hypothetical function, followed by 14 transcriptional regulation- and translation-associated genes. The results of this study indicated that although the 25W strain was highly resistant to TBT, high concentrations of TBT result in toxic effect on the transcriptional and translational levels. The target genes likely belong to a specific category of transcription- and translation-associated genes rather than to other gene categories.

Down-Regulation↗
PubMed2006

Mining ORESTES no-match database: can we still contribute to cancer transcriptome?

The Human Cancer Genome Project generated about 1 million expressed sequence tags by the ORESTES method, principally with the aim of obtaining data from cancer. Of this total, 341,680 showed no similarity with sequences in the public transcript databases, referred to as "no-match". Some of them represent low abundance or difficult to detect human transcripts, but part of these sequences represent genomic contamination or immature mRNA. We performed a bioinformatics pipeline to determine the novelty of ORESTES "no-match" datasets from prostate or breast tissues. We started with 14,908 clusters mapped on the human genome. A total of 2226 clusters originating from more than two libraries or singletons with gaps upon genome alignment were selected. Ninety-four clusters with canonical splice sites representing the most stringent criteria to be considered a gene were subjected to manual inspection regarding genomic hits. Of the manually inspected clusters, 49.6% contained new sequences where 42.2% were probable low-expression alternative forms of the characterized genes and 7.4% unpredicted genes. RT-PCR followed by sequencing was performed to validate the largest spliced sequence from 8 clusters, resulting in the confirmation of five sequences as true human transcript fragments. Some of them were differentially expressed between tumor and normal tissue by an in silico analysis. We can conclude that after clean up of the no-match dataset, we still have about 939 new exons and 165 unpredicted genes that could complete the prostate or breast transcriptome.

Breast Neoplasms↗
PubMed2006

Inflammatory response of esophageal epithelium in combined-type esophagitis in rats: a transcriptome analysis.

Recent studies have shown that esophageal mucosal inflammatory response is involved in the pathophysiology of gastro-esophageal reflux disease. The aim of the present study was to identify specific gene expression profiles of the esophageal mucosa in a rat model of combined-type chronic reflux esophagitis. Esophagogastroduodenal anastomosis was carried out in male Wistar rats by anastomosing the jejunum to the gastroesophageal junction under diethyl-ether inhalation anesthesia. Esophageal epithelial cells were obtained from esophagi of rats by laser capture microdissection. Preparation of cRNA and target hybridization were performed according to the Affymetrix GeneChip eukaryotic small sample target labeling assay protocol. The gene expression profile was evaluated by the rat toxicology U34 GeneChip. Array data analysis was carried out using Affymetrix GeneChip operating software, ingenuity pathway analysis software, and Gene Springs software. A comparison between esophagitis and sham-operated rats 2 weeks after the operation revealed that 368 probes (36%) were significantly affected, i.e. 185 probes were up-regulated, and 183 probes were down-regulated, both at levels of at least 1.5-fold in the esophagitis rats. Ingenuity signal analysis of 207 affected probes revealed the interleukin-6 signaling pathway as the most significantly affected caronical pathway. In addition, the expression of many genes associated with cytokine and transcription factor was enhanced in the esophagitis rats. This transcriptome approach provided insight into genes and putative genetic pathways thought to be affected by stimulation with gastroduodenal refluxates.

Animals↗