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Results for “Genomic profiling”

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At least 1,693 records · Page 94Linked to original sources
PubMed2004

Thrombin peptide (TP508) promotes fracture repair by up-regulating inflammatory mediators, early growth factors, and increasing angiogenesis.

Previous studies have shown that a single injection of thrombin peptide (TP508) accelerates fracture repair in a closed rat femoral fracture model. The present study was conducted to elucidate the molecular mechanisms of TP508 action using Affymetrix genome-scale profiling and to link early gene expression changes to fracture histology and bone strength changes. Treatment of femoral fractures with TP508 accelerated fracture repair as determined by destructive torsion testing. Blinded histological analysis demonstrated that TP508-treated fracture callus had a significant increase in blood vessels relative to the controls. Gene array analysis showed that TP508 significantly induced expression of early growth factors, inflammatory response modifiers, and angiogenesis-related genes. This study therefore suggests that TP508 promotes fracture repair through a mechanism that involves an increased induction of a number of growth factors, enhanced expression of inflammatory mediators, and angiogenesis-related genes.

Animals↗
PubMed2005

Signalling and gene regulation in response to ultraviolet light.

In contrast to phytochrome-, cryptochrome- and phototropin-sensing systems, about which considerable knowledge has accumulated, the ultraviolet-B (UVB) photoreceptor is not yet known at the molecular level. Information about the downstream signalling events that underlie UVB-provoked physiological responses is limited. Recent whole-genome transcript profiling, isolation of mutants that are impaired in specific UVB-induced responses and detailed photobiological studies suggest that responses that are triggered by shorter wavelength UVB and longer wavelength UVB are mediated by two different sensory systems. The bZIP transcription factor HY5 was recently identified as an important player in the long-wavelength UVB-induced signal transduction cascade. Advances in the development of luciferase-reporter lines will make it feasible to perform high-throughput genetic screens to isolate novel mutants that are impaired in sensing or transducing signals downstream of the putative UVB photoreceptor(s).

Gene Expression Regulation, Plant↗
PubMed2005

Complementary gene and protein expression studies and integrative approaches in toxicogenomics.

Parallel transcript and protein profiling is a strategy to gain further insight into the mechanisms of toxicity and disease. The technologies used to measure expression at the transcript and protein levels each convey different information and have different technical capabilities that can complement each other when combined. In this review, over twenty studies are considered for the use of -Omics platform, the chemical or disease being profiled, tissues, the number of genes and proteins found by each platform and common expression products. A strategy is suggested for toxicant expression profiling that combines the transcriptomics and proteomics of both the target tissue and blood/serum that could provide a more complete characterization of toxicity as well as synergize expression technologies toward biomarker discovery.

Animals↗
PubMed2005

Drug-induced oxidative stress in rat liver from a toxicogenomics perspective.

Macrophage activators (MA), peroxisome proliferators (PP), and oxidative stressors/reactive metabolites (OS/RM) all produce oxidative stress and hepatotoxicity in rats. However, these three classes of hepatotoxicants give three distinct gene transcriptional profiles on cDNA microarrays, an indication that rat hepatocytes respond/adapt quite differently to these three classes of oxidative stressors. The differential gene responses largely reflect differential activation of transcription factors: MA activate Stat-3 and NFkB, PP activate PPARa, and OS/RM activate Nrf2. We have used gene signature profiles for each of these three classes of hepatotoxicants to categorize over 100 paradigm (and 50+ in-house proprietary) compounds as to their oxidative stress potential in rat liver. In addition to a role for microarrays in predictive toxicology, analyses of small subsets of these signature profiles, genes within a specific pathway, or even single genes often provide important insights into possible mechanisms involved in the toxicities of these compounds.

Animals↗
PubMed2005

cDNA microarray analysis to compare HCV subgenomic replicon cells with their cured cells.

The hepatitis C virus (HCV) replicon system carrying autonomously replicating HCV subgenomic RNA in human hepatocyte cells is a potent tool for basic studies of HCV, such as viral replication and drug development. Recently, we developed two HCV subgenomic replicons (50-1 and 1B-2R1) derived from two HCV strains, 1B-1 and 1B-2, respectively. Since the expression of HCV proteins is thought to affect the host cells' gene expression profiles, we attempted to identify target genes of HCV proteins using microarray analysis (9970 genes) by comparing 50-1 and 1B-2R1 replicon cells with their "cured cells", from which the replicons had been eliminated by prolonged treatment with interferon-alpha. The results showed that HCV replicons could have a variety of expression profiles in human hepatocytes. The results also showed that 2 and 6 genes were commonly up-regulated (more than 2.0-fold) and down-regulated (less than 0.50-fold), respectively, in both 50-1 and 1B-2R1 replicon cells compared with their cured cells. The differential expression profiles of genes selected by the microarray analysis were confirmed with standard RT-PCR and real-time LightCycler PCR. It was noteworthy that the commonly down-regulated genes contained large multifunctional proteases 2 and 7, which are known as catalytic subunits of immunoproteasome, and serine proteinase inhibitor clade C. Our microarray analysis demonstrated that HCV subgenomic replicons can change the gene expression profiles of host cells, and it allowed us to compile the first list of genes that the replicons transcriptionally regulate.

Base Sequence↗
PubMed2025

Deciphering estrogen receptor alpha-driven transcription in human endometrial stromal cells via transcriptome, cistrome, and integration with chromatin landscape.

OBJECTIVE: To investigate estrogen receptor gene 1 (ESR1) and estrogen-driven transcription in human endometrial stromal cells. DESIGN: RNA sequencing (RNA-seq) and Cleavage Under Targets and Release Using Nuclease (Cut&Run) were performed on telomerase-immortalized human endometrial stromal cells with Clustered Regularly Interspaced Short Palindromic Repeats-mediated ESR1 activation. Hi-C-based chromatin architecture analysis (H3K27ac HiChIP) was conducted in primary endometrial stromal cells. SUBJECTS: Biopsies from two healthy, reproductive-aged volunteers with regular menstrual cycles and no history of gynecological malignancies. EXPOSURE: The ESR1-activated and control endometrial stromal cells were treated with estradiol (E2) or vehicle. Primary endometrial stromal cells were treated with vehicle or a decidualization cocktail. MAIN OUTCOME MEASURES: Differential gene expression analysis (RNA-seq) identified ligand-independent and -dependent ESR1 activity. Cut&Run profiled ESR1 genomic binding in ESR1-activated cells. H3K27ac HiChIP mapped hormone-induced changes in chromatin looping in primary cells. RESULTS: Among seven tested guide RNAs (gRNA), the ESR1-3 gRNA induced robust ESR1 activation and restored E2 responsiveness. Bulk RNA-seq revealed both ligand-dependent and -independent ESR1 transcriptional programs regulating inflammation, proliferation, and cancer-related pathways. Notably, 72% of differentially expressed genes overlapped with genes active in human endometrial tissue during the proliferative estrogen-dominant phase, supporting their physiological relevance. The Cut&Run-seq identified genome-wide ESR1 binding sites, with most binding sites located at distal regulatory elements. Integration of Cut&Run data with H3K27ac HiChIP chromatin loops linked distal ESR1 binding sites to gene promoters, including genes involved in decidualization (e.g., FOXO1) and endometrial cancer (e.g., ERRFI1, NRIP1, and EPAS1). Functional assays showed that ESR1 promotes cell viability and, in the presence of E2, enhances migration. CONCLUSION: The CRISPR-mediated ESR1 activation restores estrogen responsiveness in endometrial stromal cells. Combined transcriptomic, cistromic, and chromatin architecture analyses reveal ESR1's role in regulating decidualization and inflammation-related gene networks, with relevance to endometrial pathologies including endometrial cancer. This model serves as a powerful tool to study estrogen signaling in endometrial stromal cell biology and related pathologies.

Humans↗
PubMed2025

Cell-type-specific DNA methylation dynamics in the prenatal and postnatal human cortex.

The human cortex undergoes extensive epigenetic remodeling during development, although the precise temporal and cell-type-specific dynamics of DNA methylation remain incompletely understood. In this study, we profiled genome-wide DNA methylation across human cortex tissue from donors aged 6 post-conception weeks to 108 years of age. We observed widespread, developmentally regulated changes in DNA methylation, with pronounced shifts occurring during early- and mid-gestation that were distinct from age-associated modifications in the postnatal cortex. Using fluorescence-activated nuclei sorting, we optimized a protocol for the isolation of SATB2-positive neuronal nuclei, enabling the identification of cell-type-specific DNA methylation trajectories in the developing cortex. Developmentally dynamic DNA methylation sites were significantly enriched near genes implicated in autism and schizophrenia, supporting a role for epigenetic dysregulation in neurodevelopmental conditions. Our findings underscore the prenatal period as a critical window of epigenomic plasticity in the brain with important implications for understanding the genetic basis of neurodevelopmental phenotypes.

Humans↗
PubMed2004

Confirming microarray data--is it really necessary?

The generation of corroborative data has become a commonly used approach for ensuring the veracity of microarray data. Indeed, the need to conduct corroborative studies has now become official editorial policy for at least 2 journals, and several more are considering introducing such a policy. The issue of corroborating microarray data is a challenging one-there are good arguments for and against conducting such experiments. However, we believe that the introduction of a fixed requirement to corroborate microarray data, especially if adopted by more journals, is overly burdensome and may, in at least several applications of microarray technology, be inappropriate. We also believe that, in cases in which corroborative studies are deemed essential, a lack of clear guidance leaves researchers unclear as to what constitutes an acceptable corroborative study. Guidelines have already been outlined regarding the details of conducting microarray experiments. We propose that all stakeholders, including journal editorial boards, reviewers, and researchers, should undertake concerted and inclusive efforts to address properly and clarify the specific issue of corroborative data. In this article we highlight some of the thorny and vague areas for discussion surrounding this issue. We also report the results of a poll in which 76 life science journals were asked about their current or intended policies on the inclusion of corroborative studies in papers containing microarray data.

Animals↗
PubMed2004

High-accuracy amplification of nanogram total RNA amounts for gene profiling.

Microarray-based gene profiling of laser-assisted microdissected tissues or clinical biopsies is still a challenge since the amount of total RNA in such samples is limited and amplification of RNA is mandatory. Representative amplification of mRNA is highly dependent on the reverse transcription reaction, which is error prone, and on the number of amplification cycles. To improve the accuracy of RNA amplification, we optimized, combined, and tested different amplification strategies for Affymetrix oligonucleotide array hybridization. We demonstrate that different protocols differ significantly in quality of mRNA amplification. To demonstrate the accuracy and reproducibility of our optimized protocol in a clinical setting, we analyzed total RNAs from laser-assisted, microdissected cells of human prostate tissues. On the basis of these results, we recommend a standard reverse transcription reaction for small-sample-transcriptome profiling experiments as part of the Minimal Information about a Microarray Experiment (MIAME) set of standards.

Animals↗
PubMed2004

Transcriptome variations in human CaCo-2 cells: a model for enterocyte differentiation and its link to iron absorption.

Complete clinical expression of the HFE1 hemochromatosis is very likely modulated by genes linked to duodenal iron absorption, whose level is conditioned by unknown processes taking place during enterocyte differentiation. We carried out a transcriptomic study on CaCo-2 cells used as a model of enterocyte differentiation in vitro. Of the 720 genes on the microarrays, 80, 50, and 56 were significantly down-regulated up-regulated, and invariant during differentiation. With regard to iron metabolism, we showed that HEPH, SLC11A2, SLC11A3, and TF are significantly up-regulated, while ATP7B and SLC39A1 (and SFT) are down-regulated and ACO1, dCYTb, FECH, and FTH1 show constant expression. Ontological annotations highlight the decrease in the expression of cell cycle and DNA metabolism associated genes as well as transcription, protein metabolism, signal transduction, and nucleocytoplasmic transport associated genes, whereas there are increases in the expression of genes linked to cell adhesion, lipid and xenobiotic metabolism, iron transport and homeostasis, and immune response.

Caco-2 Cells↗
PubMed2006

Novel genes identified by manual annotation and microarray expression analysis in the pancreas.

The mouse PancChip, a microarray developed for studying endocrine pancreatic development and diabetes, represents over 13,000 cDNAs. After computationally assigning the cDNAs on the array to known genes, manual curation of the remaining sequences identified 211 novel transcripts. In microarray experiments, we found that 196 of these transcripts were expressed in total pancreas and/or pancreatic islets. Of 50 randomly selected clones from these 196 transcripts, 92% were confirmed as expressed by qRT-PCR. We evaluated the coding potential of the novel transcripts and found that 74% of the clones had low coding potential. Since the transcripts may be partial mRNAs, we examined their translated proteins for transmembrane or signal peptide domains and found that about 40 proteins had one of these predicted domains. Interestingly, when we investigated the novel transcripts for their overlap with noncoding microRNAs, we found that 1 of the novel transcripts overlapped a known microRNA gene.

Animals↗
PubMed2003

Distinct chromosomal imbalances in nonpolypoid and polypoid colorectal adenomas indicate different genetic pathways in the development of colorectal neoplasms.

Cytogenetic changes are widely unknown for nonpolypoid (synonymously termed as "flat" or "depressed") colorectal adenomas. A comparison with polypoid adenomas will contribute to the discussion whether different genetic pathways for colorectal tumorigenesis depending on its origin from nonpolypoid or polypoid adenomas exist. Tissue samples of nonpolypoid (n = 22), polypoid (n = 28) adenomas, carcinomas ex-nonpolypoid adenomas (n = 9), carcinomas ex-polypoid adenomas (n = 14), and normal colonic mucosa (n = 9) were investigated by comparative genomic hybridization of whole genomic DNA. Chromosomal imbalances were detected from average comparative genomic hybridization profiles for each entity. Nonpolypoid adenomas show recurrent chromosomal losses on chromosomes 16, 17p, 18, 20, and 22 and gains on chromosomes 2q, 4q, 5, 6, 8q, 12q, and 13q. In polypoid adenomas losses of whole chromosomes 16, 18, and 22 and gains of chromosomes 7q and 13 were detected. The frequency of copy number changes was higher in nonpolypoid compared to polypoid adenomas and early onset of chromosomal changes became apparent in low-grade dysplasias of nonpolypoid adenomas. Gains on chromosomes 2q, 5, 6, 8q, and 12q and losses on chromosomes 17p and 20 occurred exclusively in nonpolypoid adenomas, whereas 16p deletions are significantly more frequent in nonpolypoid than in polypoid adenomas. Carcinomas ex-nonpolypoid adenomas are characterized by more complex aberration patterns compared to nonpolypoid adenomas exhibiting frequent losses on chromosomes 8p, 12q, 14, 15q, 16, 17p, 18, and 22 and gains on 3q, 5, 6, 7, 8q, 12q, and 13, respectively. Normal colonic mucosa showed no chromosomal imbalances. Distinct differences of chromosomal imbalances between nonpolypoid and polypoid colorectal adenomas have been characterized that support the hypothesis that different genetic pathways may exist in the development of colorectal adenomas exhibiting nonpolypoid and polypoid phenotype.

Adenoma↗
PubMed2003

Expression profiling of human idiopathic dilated cardiomyopathy.

OBJECTIVE: To investigate the global changes accompanying human dilated cardiomyopathy (DCM) we performed a large-scale expression screen using myocardial biopsies from a group of DCM patients with moderate heart failure. By hierarchical clustering and functional annotation of the deregulated genes we examined extensive changes in the cellular and molecular processes associated to DCM. METHODS: The expression profiles were obtained using a whole genome covering library (UniGene RZPD1) comprising 30336 cDNA clones and amplified RNA from myocardiac biopsies from 10 DCM patients in comparison to tissue samples from four non-failing, healthy donors. RESULTS: By setting stringent selection criteria 364 differentially expressed, sequence-verified non-redundant transcripts were identified with a false discovery rate of <0.001. Numerous genes and ESTs were identified representing previously recognised, as well as novel DCM-associated transcripts. Many of them were found to be upregulated and involved in cardiomyocyte energetics, muscle contraction or signalling. Two hundred and twenty-two deregulated transcripts were functionally annotated and hierarchically clustered providing an insight into the pathophysiology of DCM. Data was validated using the MLP-deficient mouse, in which several differentially expressed transcripts identified in the human DCM biopsies could be confirmed. CONCLUSIONS: We report the first genome-wide expression profile analysis using cardiac biopsies from DCM patients at various stages of the disease. Although there is a diversity of links between the cytoskeleton and the initiation of DCM, we speculate that genes implicated in intracellular signalling and in muscle contraction are associated with early stages of the disease. Altogether this study represents the most comprehensive and inclusive molecular portrait of human cardiomyopathy to date.

Adult↗
PubMed2002

Thresholding rules for recovering a sparse signal from microarray experiments.

We consider array experiments that compare expression levels of a high number of genes in two cell lines with few repetitions and with no subject effect. We develop a statistical model that illustrates under which assumptions thresholding is optimal in the analysis of such microarray data. The results of our model explain the success of the empirical rule of two-fold change. We illustrate a thresholding procedure that is adaptive to the noise level of the experiment, the amount of genes analyzed, and the amount of genes that truly change expression level. This procedure, in a world of perfect knowledge on noise distribution, would allow reconstruction of a sparse signal, minimizing the false discovery rate. Given the amount of information actually available, the thresholding rule described provides a reasonable estimator for the change in expression of any gene in two compared cell lines.

Animals↗
PubMed2003

Use of microarrays for investigating the subtoxic effects of snake venoms: insights into venom-induced apoptosis in human umbilical vein endothelial cells.

The pathological effects of only a small percentage of the total number of protein components of snake venoms are well documented, yet this knowledge has led to a general understanding of the physiological consequences of snake venom poisoning. The aim of this study was to assess the effect of subpathological levels of Crotalus atrox (Western diamondback rattlesnake) and Bothrops jararaca (Jararaca) snake venoms on the gene expression profile of human umbilical vein endothelial cells (HUVEC) in culture. Analysis of the data demonstrated that HUVECs treated with C. atrox venom had 33 genes up-regulated with significant fold changes of 1.5 or greater compared to untreated control cells. Ten genes were down-regulated with 1.5 or greater fold changes. In cells treated with B. jararaca venom, 33 genes were observed to be up-regulated and 11 genes were down-regulated with a fold change of 1.5 or more. More than half of the up-regulated genes and approximately half of the down-regulated genes detected in cells treated with the venoms were found in both data sets underscoring both the similarities and differences between the two venoms. Ontological categorization of the up-regulated genes from endothelial cells treated with either C. atrox or B. jararaca venom gave the cell growth/maintenance and signal transducer groups as having the most members. The ontology of the down-regulated genes from both venom-treated cell samples was more varied but interestingly, the predominant ontology class was also cell growth/maintenance. Many of the up-regulated genes are involved in the Fas ligand/TNF-alpha receptor apoptotic pathway. In summary, these experiments demonstrate the power of gene expression profiling to explore the subtoxic effects of venoms on gene expression and highlight its potential for the discovery of novel insights into a variety of biological processes and signal transduction pathways. Furthermore, these studies illustrate the subtle functional differences between similar venoms that are not always evident from standard analyses.

Animals↗
PubMed2007

Microarrays to identify new therapeutic strategies for cancer.

Over the past decade, microarrays have emerged as an important tool for the characterization of cancer cells. Numerous studies have demonstrated that cDNA arrays can help delineate biological subsets of disease that have prognostic relevance. Such studies provide hope that introduction of this information into clinical trials will lead to more biologically based stratification schemes such that appropriately tailored therapies can be developed. While the identification of unique subsets of cancer promises to improve our ability to predict which cancers are unlikely to have a significant response to therapy, new therapeutic approaches are needed in most cases. The wealth of information that comes from microarray analysis of cancer likely holds the information necessary to develop such approaches. This chapter will provide examples where microarray analysis has been used in an attempt to either direct the use of current therapies or identify new potential therapeutic avenues.

Animals↗
PubMed2003

Proteomics in the postgenomic age.

Technical developments in the field of proteomics are poised to generate advances in our understanding of protein structure, function, and organization in complex signaling and regulatory networks. Improvements in mass spectrometry instrumentation, the implementation of protein arrays, and the development of robust informatics software are providing sensitive, high-throughput technologies for large-scale identification and quantitation of protein expression, protein modifications, subcellular localization, protein function, and protein-protein interactions. These advances have significant implications for understanding how cellular proteomes are regulated in health and disease.

Animals↗