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At least 487 records · Page 27Linked to original sources
PubMed2006

High-throughput genomic technology in research and clinical management of breast cancer. Evolving landscape of genetic epidemiological studies.

Candidate polymorphism-based genetic epidemiological studies have yielded little success in the search for low-penetrance breast cancer susceptibility genes. The lack of progress is partially due to insufficient coverage of genomic regions with genetic markers, as well as economic constraints, limiting both the number of genetic targets and the number of individuals being studied. Recent rapid advances in high-throughput genotyping technology and our understanding of genetic variation patterns across the human genome are now revolutionizing the way in which genetic epidemiological studies are being designed and conducted. Genetic epidemiological studies are quickly progressing from candidate gene studies to comprehensive pathway investigation and, further, to genomic epidemiological studies where the whole human genome is being interrogated to identify susceptibility alleles. This paper reviews the evolving approaches in the search for low-penetrance breast cancer susceptibility gene variants and discusses their potential promises and pitfalls.

Breast Neoplasms↗
PubMed2004

Global transcription analysis of immature avian erythrocytic progenitors: from self-renewal to differentiation.

The molecular mechanisms regulating the cell fate decision between self-renewal and differentiation/apoptosis in stem and progenitor cells are poorly understood. Here, we report the first comprehensive identification of genes potentially involved in the switch from self-renewal toward differentiation of primary, non-immortalized erythroid avian progenitor cells (T2EC cells). We used the Serial Analysis of Gene Expression (SAGE) technique in order to identify and quantify the genome fraction functionally active in a self-renewing versus a differentiating cell population. We generated two SAGE libraries and sequenced a total of 37,589 tags, thereby obtaining the first transcriptional profile characterization of a chicken cell. Tag identification was performed using a new relational database (Identitag) developed in the laboratory, which allowed a highly satisfactory level of identification. Among 123 differentially expressed genes, 11 were investigated further and for nine of them the differential expression was subsequently confirmed by real-time PCR. The comparison of tag abundance between the two libraries revealed that only a small fraction of transcripts was differentially expressed. The analysis of their functions argue against a prominent role for a master switch in T2EC cells decision-making, but are in favor of a critical role for coordinated small variations in a relatively small number of genes that can lead to essential cellular identity changes.

Animals↗
PubMed2026

Whole genome and exome sequencing of pancreatic neuroendocrine tumour to investigate PRRT response.

Patients with pancreatic neuroendocrine tumours (PNETs) often have similar baseline clinical characteristics, including grade and molecular imaging phenotype, yet have highly variable responses to peptide receptor radionuclide therapy (PRRT). To identify genomic alterations and mutational patterns associated with PRRT treatment response and acquired somatic changes following PRRT exposure, whole genome or exome sequencing was applied to 40 PNET samples from 32 patients, including eight paired pre- or post-PRRT samples. The genomic profile of tumours reflected the known mutational landscape of PNET with MEN1 (34%), ATRX/DAXX (47%) alterations and a recurrent pattern of aneuploidy (38%) detected. A recurrent PSIP1::TBL1X fusion of unknown function was also identified in four tumours. The disease control rate following PRRT using RECIST1.1 and molecular imaging criteria was 88% (28/32). No mutational features were found to be statistically associated with progression-free survival. There was no significant increase in tumour mutational burden in the post-PRRT tumours, nor recurrent emergent mutational changes in cancer driver genes to explain progression to higher-grade disease, when observed. However, a small indel signature (ID8) previously associated with DNA damage repair by non-homologous end joining (NHEJ) was higher in PRRT-exposed compared with PRRT-naive samples (23.8 vs 4.8%, respectively; P < 0.001). Thus, comprehensive DNA analysis of pancreatic NETs did not identify biomarkers predictive of PRRT response nor evidence for high-level PRRT-induced genomic instability or hypermutation, yet mutation signature analysis supports NHEJ as being important for DNA repair and survival of neuroendocrine cells following exposure to beta-particle radiation.

Humans↗
PubMed2006

Cytogenetically balanced translocations are associated with focal copy number alterations.

Current cytogenetic methods (e.g., G-banding and multicolor chromosomal painting) allow detection of translocation events but lack the resolution to (a) locate the breakpoints precisely at the chromosome band level or (b) discriminate balanced translocations from translocations with copy number alterations not previously reported, or imperfectly balanced translocations. In this study, we demonstrate that cytogenetically balanced translocations are in fact frequently associated with segmental gain or loss of DNA. The recent development of a whole genome tiling path BAC array has enabled tiling resolution analysis of genomic segmental copy number status. Combining tiling resolution BAC array comparative genomic hybridization (array CGH) with G-Banding analysis and multicolor chromosomal painting approaches such as spectral karyotyping (SKY) facilitates high-resolution mapping of genomic alterations associated with imperfectly balanced translocations. Using a refined version of our CGH array we have deduced the copy number status throughout the genomes of three cytogenetically well-characterized prostate cancer cell lines (PC3, DU145, LNCaP) to determine whether translocations are associated with focal gains and losses of DNA. At 78 kb tiling resolution we identified the boundaries of 170, 80, and 34 known and novel copy number alterations (CNA) in these cell line genomes, respectively. Thirty-three of the 36 known translocations (92%, P < 0.001) in DU145 were associated with segmental CNA. Likewise, 80% (P < 0.001) of the known translocations showed association in LNCaP. Although many translocation breakpoints exhibit segmental alteration in PC3, the pattern of chromosomal rearrangements is too complex for use in comprehensive association with CNA boundaries. Our results reveal that imperfectly balanced translocations in tumor genomes are a phenomenon that occurs at frequencies much higher than previously demonstrated.

Cell Line, Tumor↗
PubMed2006

[Proteomics of breast cancer: From differential to functional analysis].

From differential analysis to identify biomarkers, to functional analysis for finding new therapeutic targets, proteomics bring new comprehensive information for a better understanding of the molecular basis of oncology and new perspectives for the clinic. However the major limitation of proteomic investigations, more generally of post-genomic approaches, remains the molecular and cellular complexity of the mammary gland that is still a major challenge.

Biomarkers, Tumor↗
PubMed2025

Cell-type-specific enrichment of somatic aneuploidy in the mammalian brain.

Somatic mutations alter the genomes of a subset of an individual's brain cells, impacting gene regulation and contributing to disease processes. Mosaic single-nucleotide variants have been characterized with single-cell resolution in the brain, but we have limited information about large-scale structural variation such as whole-chromosome duplication or loss. We used a dataset of over 415,000 single-cell DNA methylation and chromatin conformation profiles from the adult mouse brain to comprehensively identify and characterize aneuploid cells. Somatic trisomy events were strongly enriched on chromosome 16, which is syntenic with human chromosome 21. We also observed a specific enrichment of chromosome gain and loss events in specific cell types, including Pons neurons and oligodendrocyte precursor cells. Chromosome 16 trisomy occurred in multiple cell types and across brain regions, suggesting that nondisjunction is a recurrent feature of somatic structural variation in the brain.

Animals↗
PubMed2025

An RNA polymerase III tissue and tumor atlas uncovers context-specific activities linked to 3D epigenome regulatory mechanisms.

RNA polymerase III (Pol III) produces a plethora of small noncoding RNA species involved in diverse cellular processes, from transcription regulation and splicing to RNA stability, translation, and proteostasis. Though Pol III activity is broadly coupled with cellular demands for protein synthesis and growth, a more precise understanding of gene-level dynamics and context-specific expression patterns remains missing, in part due to challenges related to sequencing and mapping Pol III-derived small ncRNAs. Here, we establish a predictive multi-tissue map of human Pol III activity across 19 tissues and 23 primary cancer subtypes by comprehensively profiling the chromatin accessibility of canonical Pol III-transcribed gene classes. Our framework relies on the unique relationship between gene accessibility and Pol III transcription, inferring activity through uniform binary classification of ATAC-seq enrichment at Pol III-transcribed genes. By characterizing multi-context gene uniformity, we provide a definition of the core Pol III transcriptome, broadly active across specialized tissues, and catalog genes with varied levels of context specificity. Our genomic Pol III atlas uncovers variable levels of activity across tissues, including sharp contraction of the Pol III transcriptome in heart and brain tissues and frequent expansion across diverse cancers. We show that both tissue- and tumor-specific genes are significantly enriched within lamina-associated domains (LADs), and that aberrant expression of nuclear lamin proteins is sufficient to induce Pol III-emergent patterns at tumor-specific genes. Together, these findings link Pol III dynamics to subnuclear compartmentalization and provide a resource for better understanding Pol III expansion and small RNA biogenesis in cancer.

Journal Article↗
PubMed2004

Transcriptome analysis of haploid male gametophyte development in Arabidopsis.

BACKGROUND: The haploid male gametophyte generation of flowering plants consists of two- or three-celled pollen grains. This functional specialization is thought to be a key factor in the evolutionary success of flowering plants. Moreover, pollen ontogeny is also an attractive model in which to dissect cellular networks that control cell growth, asymmetric cell division and cellular differentiation. Our objective, and an essential step towards the detailed understanding of these processes, was to comprehensively define the male haploid transcriptome throughout development. RESULTS: We have developed staged spore isolation procedures for Arabidopsis and used Affymetrix ATH1 genome arrays to identify a total of 13,977 male gametophyte-expressed mRNAs, 9.7% of which were male-gametophyte-specific. The transition from bicellular to tricellular pollen was accompanied by a decline in the number of diverse mRNA species and an increase in the proportion of male gametophyte-specific transcripts. Expression profiles of regulatory proteins and distinct clusters of coexpressed genes were identified that could correspond to components of gametophytic regulatory networks. Moreover, integration of transcriptome and experimental data revealed the early synthesis of translation factors and their requirement to support pollen tube growth. CONCLUSIONS: The progression from proliferating microspores to terminally differentiated pollen is characterized by large-scale repression of early program genes and the activation of a unique late gene-expression program in maturing pollen. These data provide a quantum increase in knowledge concerning gametophytic transcription and lay the foundations for new genomic-led studies of the regulatory networks and cellular functions that operate to specify male gametophyte development.

Arabidopsis↗
PubMed2005

Expression profile of two storage-protein gene families in hexaploid wheat revealed by large-scale analysis of expressed sequence tags.

To discern expression patterns of individual storage-protein genes in hexaploid wheat (Triticum aestivum cv Chinese Spring), we analyzed comprehensive expressed sequence tags (ESTs) of common wheat using a bioinformatics technique. The gene families for alpha/beta-gliadins and low molecular-weight glutenin subunit were selected from the EST database. The alignment of these genes enabled us to trace the single nucleotide polymorphism sites among both genes. The combinations of single nucleotide polymorphisms allowed us to assign haplotypes into their homoeologous chromosomes by allele-specific PCR. Phylogenetic analysis of these genes showed that both storage-protein gene families rapidly diverged after differentiation of the three genomes (A, B, and D). Expression patterns of these genes were estimated based on the frequencies of ESTs. The storage-protein genes were expressed only during seed development stages. The alpha/beta-gliadin genes exhibited two distinct expression patterns during the course of seed maturation: early expression and late expression. Although the early expression genes among the alpha/beta-gliadin and low molecular-weight glutenin subunit genes showed similar expression patterns, and both genes from the D genome were preferentially expressed rather than those from the A or B genome, substantial expression of two early expression genes from the A genome was observed. The phylogenetic relationships of the genes and their expression patterns were not correlated. These lines of evidence suggest that expression of the two storage-protein genes is independently regulated, and that the alpha/beta-gliadin genes possess novel regulation systems in addition to the prolamin box.

Base Sequence↗
PubMedDate not supplied

Gene and protein profiling of the response of MA-10 Leydig tumor cells to human chorionic gonadotropin.

Activation of the steroidogenic machinery by peptide hormones involves a number of steps for transmitting signals from the plasma membrane to mitochondria in a spatially and temporally coordinated manner. Although key proteins mediating the hormonal signal have been identified, recent data suggest that the pathway might involve more complex protein-protein and protein-lipid interactions. Genomic and proteomic methods of analysis, namely the Affymetrix Murine Genome U74A v2 GeneChip and the BD PowerBlot Western Array, were used to identify human chorionic gonadotropin (hCG)-induced changes in mRNA and protein of MA-10 Leydig tumor cells that parallel the increase seen in progesterone synthesis. To analyze the massive amount of data that was generated, a comprehensive protein information matrix summarizing the features of each gene or protein, including its known properties, as well as annotations derived by homology-based functional inference, was developed. Of the genes examined by Affymetrix array, approximately 79 were differentially expressed and of gene products examined by PowerBlot, 9 were differentially expressed (above twofold). Changes in the expression of selected transcripts of interest were confirmed using real-time quantitative polymerase chain reaction and immunoblot analyses. Collectively, these results indicate that hormonal regulation of steroidogenesis is a complex phenomenon, involving proteins that participate in various known and novel pathways, which are implicated in transmitting signals from the plasma membrane to mitochondria and nucleus.

Blotting, Western↗
PubMed2005

Devising transcriptional regulatory networks operating during the cell cycle and differentiation using ChIP-on-chip.

The study of global transcriptional regulatory networks in eukaryotes has advanced rapidly in the last five years with the advent of genomic microarrays that allow investigators to comprehensively scrutinize the structure and composition of transcriptomes and chromatin. Many facets of this field have benefited from an examination of the location of proteins associated with chromatin. We describe here how we have used genomic arrays to perform location analysis (or ChIP-on-chip analysis) of regulatory factors that control the complex process of cell cycle progression and differentiation, in order to identify key direct transcriptional targets. Combining this information with data obtained through expression profiling and computational analysis of transcription factor binding sites has also allowed us to devise transcriptional regulatory networks governing these processes.

Animals↗
PubMed2005

From genomics via proteomics to cellular physiology of the Gram-positive model organism Bacillus subtilis.

Complementing proteomic technologies enable an unbiased view of cellular adaptation and thus may provide a new understanding of cellular physiology, particularly for microorganisms because a major fraction of their proteome is accessible to currently available technology. In combination with transcriptional profiling expression proteomics provides access to interesting candidate genes and proteins that will then need to be validated and supplemented by traditional physiological, biochemical and genetic approaches. After a description of the current status of the technology, we display the potential of microbial proteomics using the model organism Bacillus subtilis as example. Starting from a proteome map a proteomic view of the metabolism will be provided. Furthermore, we demonstrate that proteomics complemented by transcriptomics is also useful for the study of stress and starvation responses and that integration of these data will lead to a comprehensive understanding of the adaptational network of bacterial cells. Thus, B. subtilis constitutes a highly versatile and tractable model organism for the study of generic stress responses and the expertise that has been gained can easily be transferred to the study of the cellular physiology of related Gram-positive pathogens and their pathophysiology.

Bacillus subtilis↗
PubMed2003

The sigmaE regulon and the identification of additional sporulation genes in Bacillus subtilis.

We report the identification and characterization on a genome-wide basis of genes under the control of the developmental transcription factor sigma(E) in Bacillus subtilis. The sigma(E) factor governs gene expression in the larger of the two cellular compartments (the mother cell) created by polar division during the developmental process of sporulation. Using transcriptional profiling and bioinformatics we show that 253 genes (organized in 157 operons) appear to be controlled by sigma(E). Among these, 181 genes (organized in 121 operons) had not been previously described as members of this regulon. Promoters for many of the newly identified genes were located by transcription start site mapping. To assess the role of these genes in sporulation, we created null mutations in 98 of the newly identified genes and operons. Of the resulting mutants, 12 (in prkA, ybaN, yhbH, ykvV, ylbJ, ypjB, yqfC, yqfD, ytrH, ytrI, ytvI and yunB) exhibited defects in spore formation. In addition, subcellular localization studies were carried out using in-frame fusions of several of the genes to the coding sequence for GFP. A majority of the fusion proteins localized either to the membrane surrounding the developing spore or to specific layers of the spore coat, although some fusions showed a uniform distribution in the mother cell cytoplasm. Finally, we used comparative genomics to determine that 46 of the sigma(E)-controlled genes in B.subtilis were present in all of the Gram-positive endospore-forming bacteria whose genome has been sequenced, but absent from the genome of the closely related but not endospore-forming bacterium Listeria monocytogenes, thereby defining a core of conserved sporulation genes of probable common ancestral origin. Our findings set the stage for a comprehensive understanding of the contribution of a cell-specific transcription factor to development and morphogenesis.

Bacillus subtilis↗
PubMed2004

Widespread distribution of antisense transcripts in the Plasmodium falciparum genome.

The availability of the complete genome sequence of Plasmodium falciparum has facilitated high-throughput profiling of its complex life cycle, following the application of micro-array, proteomic, and serial analysis of gene expression (SAGE) technologies in this system. These, in turn, have yielded unprecedented insight into global gene expression, including the foremost demonstration of antisense transcription in the parasite. For example, owing to its inherent ability to sample novel ORFs and to predict transcript orientation, SAGE analysis in asexual forms led to the initial discovery of highly abundant antisense RNAs. To determine the extent of this phenomenon in P. falciparum, we have surveyed the distribution of both sense and antisense transcripts across the asexual transcriptome for the first time. To this end, a relational database integrating SAGE expression data with genome annotation information was constructed. This allowed the comprehensive annotation of a total of 17245 SAGE tags, extending over a 350-fold expression range. Transcripts from approximately 30% of the estimated 3D7 gene loci were present at detectable levels in mixed asexual stages, where loci involved in invasion and immune evasion; and carbohydrate metabolism were highly represented in the sense transcriptome. Approximately 12% of SAGE tags, however, were derived from the non-coding strand of nuclear-encoded ORFs, indicating that endogenous antisense RNAs are widespread in this system. Notably, these antisense transcripts were absent from the mitochondrial genome. Interestingly, we note that sense and antisense tag counts from single loci across the transcriptome were inversely related. Taken together, this data may provide first hints as to the possible function of antisense transcription in this system.

Animals↗
PubMed2006

Plant metabolomics: towards biological function and mechanism.

Metabolite profiling is a fast growing technology and is useful for phenotyping and diagnostic analyses of plants. It is also rapidly becoming a key tool in functional annotation of genes and in the comprehensive understanding of the cellular response to biological conditions. Metabolomics approaches have recently been used to assess the natural variance in metabolite content between individual plants, an approach with great potential for the improvement of the compositional quality of crops. Here, we assess the contribution of metabolite profiling to these areas.

Botany↗
PubMed2025

Elevated circulating IL-8 correlates with poor prognosis in urological cancers: a meta-analysis and bioinformatic validation.

BACKGROUND: Interleukin-8 (IL-8) is a key cytokine that has been implicated in multiple aspects of cancer progression and therapeutic resistance. Elevated levels of circulating IL-8&#xa0;(cIL-8) have been implicated in adverse clinical outcomes among patients with urological cancers. However, definitive evidence consolidating these observations remains lacking. The present study aims to synthesize the existing research findings to provide a comprehensive, evidence-based reference for clinical practice. METHODS: A systematic literature search was conducted to identify relevant studies that reported on the prognostic impact of cIL-8 levels in urological cancer patients. Hazard ratios (HRs) for overall survival (OS) and progression-free survival (PFS) were extracted and pooled to estimate the overall effect. Furthermore, Kaplan-Meier's survival analyses were conducted using RNA-seq data from The Cancer Genome Atlas (TCGA) through the Gene Expression Profiling Interactive Analysis 2 (GEPIA 2) online tool to validate the observed associations. RESULTS: A total of 19 cohorts encompassing 2740 patients from 12 studies were included in the meta-analysis. The findings revealed that elevated cIL-8 levels were significantly associated with inferior OS (HR: 1.86; 95% confidence intervals (CI): 1.72-2.02) and PFS (HR: 1.59; 95%CI: 1.25-2.03) in patients with urological cancers. The consistency and validity of these results were further supported by survival analyses performed using the GEPIA 2 tool. CONCLUSIONS: This study, which is the first meta-analysis to systematically examine the prognostic significance of cIL-8 in urological cancers, supported by bioinformatics validation, confirms that elevated cIL-8 levels serve as a potential biomarker for predicting adverse outcomes. Our findings underscore the importance of targeting IL-8 as a therapeutic strategy to overcome treatment resistance and improve outcomes for urological cancer patients. Further research into IL-8-targeted therapies and their integration into clinical practice is urgently needed to enhance the treatment landscape for urological cancers.

Humans↗
PubMed2005

A gene expression fingerprint of C. elegans embryonic motor neurons.

BACKGROUND: Differential gene expression specifies the highly diverse cell types that constitute the nervous system. With its sequenced genome and simple, well-defined neuroanatomy, the nematode C. elegans is a useful model system in which to correlate gene expression with neuron identity. The UNC-4 transcription factor is expressed in thirteen embryonic motor neurons where it specifies axonal morphology and synaptic function. These cells can be marked with an unc-4::GFP reporter transgene. Here we describe a powerful strategy, Micro-Array Profiling of C. elegans cells (MAPCeL), and confirm that this approach provides a comprehensive gene expression profile of unc-4::GFP motor neurons in vivo. RESULTS: Fluorescence Activated Cell Sorting (FACS) was used to isolate unc-4::GFP neurons from primary cultures of C. elegans embryonic cells. Microarray experiments detected 6,217 unique transcripts of which approximately 1,000 are enriched in unc-4::GFP neurons relative to the average nematode embryonic cell. The reliability of these data was validated by the detection of known cell-specific transcripts and by expression in UNC-4 motor neurons of GFP reporters derived from the enriched data set. In addition to genes involved in neurotransmitter packaging and release, the microarray data include transcripts for receptors to a remarkably wide variety of signaling molecules. The added presence of a robust array of G-protein pathway components is indicative of complex and highly integrated mechanisms for modulating motor neuron activity. Over half of the enriched genes (537) have human homologs, a finding that could reflect substantial overlap with the gene expression repertoire of mammalian motor neurons. CONCLUSION: We have described a microarray-based method, MAPCeL, for profiling gene expression in specific C. elegans motor neurons and provide evidence that this approach can reveal candidate genes for key roles in the differentiation and function of these cells. These methods can now be applied to generate a gene expression map of the C. elegans nervous system.

Animals↗
PubMed2026

CasY7: An optimized Cas12i system for enhanced genome editing in monocot crops.

The CRISPR-Cas12 family nucleases, particularly the Cas12i subtypes, are considered promising alternatives to Cas9 for genome editing in plants. We previously developed a new Cas12i variant, CasY7, which has been successfully applied in clinical trials; its performance in plants remains to be investigated. Initial testing in stable transgenic maize and rice showed that the codon-optimized CasY7 (pCasY7e1) achieved average editing efficiencies of 58.7% and 62.3% across five target sites, respectively, outperforming the typical Cpf1 (pCpf1) control that targets the same sites. To further enhance activity, we fused T5 exonuclease to CasY7 (pCasY7e2), which shifted mutation profiles toward larger deletions, and subsequently integrated an MS2 aptamer into the crRNA scaffold (pCasY7e3). The optimized pCasY7e3 system increased editing efficiencies to 87.7% in maize and 82.9% in rice-approximately 2.7-fold higher than pCpf1. We further demonstrated multiplexed editing in maize, generating biallelic dwarf mutants, and validated functionality in hexaploid wheat with editing efficiencies up to 58.8%. Overall, our comprehensive validation across 942 transgenic plants confirmed robust editing in maize, rice, and wheat, establishing CasY7 as a high-efficiency addition to the CRISPR toolkit.

Zea mays↗