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  • 1
    Keywords: CELLS ; EXPRESSION ; CELL ; human ; NETWORKS ; SITE ; SITES ; DISTINCT ; GENE ; GENE-EXPRESSION ; GENES ; GENOME ; microarray ; RNA ; transcription ; LINES ; MECHANISM ; mechanisms ; IDENTIFICATION ; PATTERNS ; gene expression ; microarrays ; PROMOTER ; PROMOTERS ; genetics ; HUMAN GENOME ; HUMAN GENES ; METHYLATION ; heredity ; PATTERN ; GENOME-WIDE ANALYSIS ; ARRAY ; genomics ; RESOURCE ; analysis ; CHIP ; USA ; microbiology ; ENGLAND ; biotechnology ; PLATFORM ; BREAST-CANCER CELLS ; synthesis ; STATE ; GENOME-WIDE ; ESTROGEN-RECEPTOR-ALPHA ; TRANSCRIPTION INITIATION
    Abstract: Background: Independent lines of evidence suggested that a large fraction of human genes possess multiple promoters driving gene expression from distinct transcription start sites. Understanding which promoter is employed in which cellular context is required to unravel gene regulatory networks within the cell. Results: We have developed a custom microarray platform that tiles roughly 35,000 alternative putative promoters from nearly 7,000 genes in the human genome. To demonstrate the utility of this array platform, we have analyzed the patterns of promoter usage in 17 beta-estradiol (E2)-treated and untreated MCF7 cells and show widespread usage of alternative promoters. Most intriguingly, we show that the downstream promoter in E2-sensitive multiple promoter genes tends to be very close to the 3'-terminus of the gene, suggesting exotic mechanisms of expression regulation in these genes. Conclusion: The usage of alternative promoters greatly multiplies the transcriptional complexity available within the human genome. The fact that many of these promoters are incapable of driving the synthesis of a meaningful protein-encoding transcript further complicates the story
    Type of Publication: Journal article published
    PubMed ID: 18655706
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  • 2
    Keywords: CANCER ; EXPRESSION ; SURVIVAL ; tumor ; carcinoma ; CELL ; LUNG ; MODEL ; THERAPY ; CLASSIFICATION ; lung cancer ; LUNG-CANCER ; DEATH ; DISEASE ; RISK ; PROTEIN ; SAMPLE ; SAMPLES ; transcription ; TUMORS ; PATIENT ; DNA ; TRANSCRIPTION FACTOR ; BREAST-CANCER ; TARGET ; STAGE ; IDENTIFICATION ; PATTERNS ; METASTASIS ; chemotherapy ; DNA methylation ; HETEROZYGOSITY ; PROGNOSTIC-FACTORS ; MULTIVARIATE ; CARCINOMAS ; PROGNOSTIC FACTORS ; adenocarcinoma ; ADENOCARCINOMAS ; squamous cell carcinoma ; TARGETS ; METHYLATION ; PROGNOSTIC FACTOR ; staging ; protein expression ; RELATIVE RISK ; CELL CARCINOMA ; SUBSET ; PATTERN ; THERAPIES ; overall survival ; LIBRARIES ; PROGNOSTIC-FACTOR ; CPG ISLANDS ; LEVEL ; INTERVAL ; methods ; EXPRESSION PROFILES ; ADJUVANT CHEMOTHERAPY ; USA ; NSCLC ; genomic ; SQUAMOUS-CELL ; PREDICT ; MEDICINE ; nonsmall cell lung cancer ; correlates ; DNA-METHYLATION ; scanning ; LONG ARM ; SQUAMOUS-CELL-CARCINOMAS
    Abstract: Background Lung cancer is the leading cause of cancer-related death worldwide. Currently, tumor, node, metastasis (TNM) staging provides the most accurate prognostic parameter for patients with non-small cell lung cancer (NSCLC). However, the overall survival of patients with resectable tumors varies significantly, indicating the need for additional prognostic factors to better predict the outcome of the disease, particularly within a given TNM subset. Methods and Findings In this study, we investigated whether adenocarcinomas and squamous cell carcinomas could be differentiated based on their global aberrant DNA methylation patterns. We performed restriction landmark genomic scanning on 40 patient samples and identified 47 DNA methylation targets that together could distinguish the two lung cancer subgroups. The protein expression of one of those targets, oligodendrocyte transcription factor 1 (OLIG1), significantly correlated with survival in NSCLC patients, as shown by univariate and multivariate analyses. Furthermore, the hazard ratio for patients negative for OLIG1 protein was significantly higher than the one for those patients expressing the protein, even at low levels. Conclusions Multivariate analyses of our data confirmed that OLIG1 protein expression significantly correlates with overall survival in NSCLC patients, with a relative risk of 0.84 (95% confidence interval 0.77-0.91, p 〈 0.001) along with T and N stages, as indicated by a Cox proportional hazard model. Taken together, our results suggests that OLIG1 protein expression could be utilized as a novel prognostic factor, which could aid in deciding which NSCLC patients might benefit from more aggressive therapy. This is potentially of great significance, as the addition of postoperative adjuvant chemotherapy in T2N0 NSCLC patients is still controversial
    Type of Publication: Journal article published
    PubMed ID: 17388669
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  • 3
    Keywords: CANCER ; CELLS ; EXPRESSION ; tumor ; TUMOR-CELLS ; CELL ; human ; IN-VIVO ; MODEL ; MODELS ; VIVO ; CLASSIFICATION ; COMMON ; DISEASE ; DISTINCT ; GENE ; SAMPLE ; SAMPLES ; transcription ; TISSUE ; TUMORS ; DNA ; MECHANISM ; mechanisms ; T cell ; T-CELL ; BIOLOGY ; SEQUENCE ; SEQUENCES ; SUSCEPTIBILITY ; BREAST-CANCER ; culture ; MOUSE ; STAGE ; PROGRESSION ; LYMPHOMA ; PATTERNS ; PROMOTER ; TUMOR PROGRESSION ; genetics ; COLORECTAL-CANCER ; DNA methylation ; inactivation ; p53 ; EVOLUTION ; PHENOTYPE ; MOUSE MODEL ; SELECTION ; specificity ; OVEREXPRESSION ; METHYLATION ; TUMOR CELLS ; heredity ; CHRONIC LYMPHOCYTIC-LEUKEMIA ; HYPERMETHYLATION ; HETEROGENEITY ; EPIGENETIC INACTIVATION ; targeting ; PROGRAM ; PATTERN ; TUMOR-SUPPRESSOR ; HUMAN CANCER ; ACUTE MYELOID-LEUKEMIA ; LIBRARIES ; CELL LYMPHOMA ; CPG ISLANDS ; GENE-TRANSCRIPTION ; development ; TUMOR-CELL ; SUPPRESSOR ; PROFILES ; EVENTS ; SIGNATURE ; DISEASE PROGRESSION ; USA ; CPG ISLAND HYPERMETHYLATION ; HUMAN CANCERS ; PROMOTER METHYLATION ; CANCERS ; in vivo ; genomic ; GENETIC ALTERATION ; RARE ; PREDICT ; CpG island ; MYC ; TUMOR-DEVELOPMENT ; DNA-METHYLATION ; scanning ; CELL LYMPHOMAS ; evidence ; TUMOR SUPPRESSORS ; CAUSAL ROLE ; DNA HYPOMETHYLATION
    Abstract: Hypermethylation of CpG islands is a common epigenetic alteration associated with cancer. Global patterns of hypermethylation are tumor-type specific and nonrandom. The biological significance and the underlying mechanisms of tumor-specific aberrant promoter methylation remain unclear, but some evidence suggests that this specificity involves differential sequence susceptibilities, the targeting of DNA methylation activity to specific promoter sequences, or the selection of rare DNA methylation events during disease progression. Using restriction landmark genomic scanning on samples derived from tissue culture and in vivo models of T cell lymphomas, we found that MYC overexpression gave rise to a specific signature of CpG island hypermethylation. This signature reflected gene transcription profiles and was detected only in advanced stages of disease. The further inactivation of the Pten, p53, and E2f2 tumor suppressors in MYC-induced lymphomas resulted in distinct and diagnostic CpG island methylation signatures. Our data suggest that tumor-specific DNA methylation in lymphomas arises as a result of the selection of rare DNA methylation events during the course of tumor development. This selection appears to be driven by the genetic configuration of tumor cells, providing experimental evidence for a causal role of DNA hypermethylation in tumor progression and an explanation for the tremendous epigenetic heterogeneity observed in the evolution of human cancers. The ability to predict genome-wide epigenetic silencing based on relatively few genetic alterations will allow for a more complete classification of tumors and understanding of tumor cell biology
    Type of Publication: Journal article published
    PubMed ID: 17907813
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  • 4
    Keywords: CANCER ; CELL ; human ; IN-VIVO ; DISEASE ; DISEASES ; GENE ; GENES ; GENOME ; PROTEIN ; transcription ; TISSUE ; MECHANISM ; MESSENGER-RNA ; mechanisms ; BREAST-CANCER ; PROMOTER ; PROMOTERS ; genetics ; HUMAN GENOME ; TRENDS ; heredity ; TISSUE-SPECIFIC EXPRESSION ; molecular ; review ; ANNOTATION ; GENE PROMOTER ; GERM-CELLS ; human brain ; MOLECULAR-MECHANISMS ; gene regulation ; USA ; ENGLAND ; RECEPTOR GENE ; GENOMES ; GENE PROMOTERS ; TATA-BOX
    Abstract: We are beginning to appreciate the increasing complexity of mammalian gene structure. A phenomenon that adds an important dimension to this complexity is the use of alternative gene promoters that drive widespread cell type, tissue type or developmental gene regulation. Recent annotations of the human genome suggest that almost one half of the protein-coding genes contain alternative promoters, including those of many disease-associated genes. Aberrant use of one promoter over another has been found to be associated with various diseases, including cancer. Here we discuss the functional consequences of use and misuse of alternative promoters in normal and disease genomes and review the molecular mechanisms regulating alternative promoter use in mammalian genomes
    Type of Publication: Journal article published
    PubMed ID: 18329129
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