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  • 1
    Abstract: A characteristic feature of anaplastic large cell lymphoma is the significant repression of the T-cell expression program despite its T-cell origin. The reasons for this down-regulation of T-cell phenotype are still unknown. To elucidate whether epigenetic mechanisms are responsible for the loss of the T-cell phenotype, we treated anaplastic large cell lymphoma and T-cell lymphoma/leukemia cell lines (n=4, each) with epigenetic modifiers to evoke DNA demethylation and histone acetylation. Global gene expression data from treated and untreated cell lines were generated and selected, and differentially expressed genes were evaluated by real-time reverse transcriptase polymerase chain reaction and western blot analysis. Additionally, histone H3 lysine 27 trimethylation was analyzed by chromatin immunoprecipitation. Combined DNA demethylation and histone acetylation of anaplastic large cell lymphoma cells was not able to reconstitute their T-cell phenotype. Instead, the same treatment induced in T cells: (i) an up-regulation of anaplastic large cell lymphoma-characteristic genes (e.g. ID2, LGALS1, c-JUN), and (ii) an almost complete extinction of their T-cell phenotype including CD3, LCK and ZAP70. In addition, suppressive trimethylation of histone H3 lysine 27 of important T-cell transcription factor genes (GATA3, LEF1, TCF1) was present in anaplastic large cell lymphoma cells, which is in line with their absence in primary tumor specimens as demonstrated by immunohistochemistry. Our data suggest that epigenetically activated suppressors (e.g. ID2) contribute to the down-regulation of the T-cell expression program in anaplastic large cell lymphoma, which is maintained by trimethylation of histone H3 lysine 27.
    Type of Publication: Journal article published
    PubMed ID: 22899583
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  • 2
    Abstract: MOTIVATION: Integrating heterogeneous datasets from several sources is a common bioinformatics task that often requires implementing a complex workflow intermixing database access, data filtering, format conversions, identifier mapping, among further diverse operations. Data integration is especially important when annotating next generation sequencing data, where a multitude of diverse tools and heterogeneous databases can be used to provide a large variety of annotation for genomic locations, such a single nucleotide variants or genes. Each tool and data source is potentially useful for a given project and often more than one are used in parallel for the same purpose. However, software that always produces all available data is difficult to maintain and quickly leads to an excess of data, creating an information overload rather than the desired goal-oriented and integrated result. RESULTS: We present SoFIA, a framework for workflow-driven data integration with a focus on genomic annotation. SoFIA conceptualizes workflow templates as comprehensive workflows that cover as many data integration operations as possible in a given domain. However, these templates are not intended to be executed as a whole; instead, when given an integration task consisting of a set of input data and a set of desired output data, SoFIA derives a minimal workflow that completes the task. These workflows are typically fast and create exactly the information a user wants without requiring them to do any implementation work. Using a comprehensive genome annotation template, we highlight the flexibility, extensibility and power of the framework using real-life case studies. AVAILABILITY AND IMPLEMENTATION: https://github.com/childsish/sofia/releases/latest under the GNU General Public License CONTACT: liam.childs@hu-berlin.de SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
    Type of Publication: Journal article published
    PubMed ID: 27187206
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  • 3
    Keywords: EXPRESSION ; IN-VIVO ; GENES ; METABOLISM ; CELL-CYCLE ; TUMOR PROGRESSION ; COLORECTAL-CANCER ; REGULATORY ELEMENTS ; DNA-DAMAGE RESPONSE ; RHYTHMS
    Abstract: Circadian rhythms are essential to the temporal regulation of molecular processes in living systems and as such to life itself. Deregulation of these rhythms leads to failures in biological processes and eventually to the manifestation of pathological phenotypes including cancer. To address the questions as to what are the elicitors of a disrupted clock in cancer, we applied a systems biology approach to correlate experimental, bioinformatics and modelling data from several cell line models for colorectal and skin cancer. We found strong and weak circadian oscillators within the same type of cancer and identified a set of genes, which allows the discrimination between the two oscillator-types. Among those genes are IFNGR2, PITX2, RFWD2, PPARgamma, LOXL2, Rab6 and SPARC, all involved in cancer-related pathways. Using a bioinformatics approach, we extended the core-clock network and present its interconnection to the discriminative set of genes. Interestingly, such gene signatures link the clock to oncogenic pathways like the RAS/MAPK pathway. To investigate the potential impact of the RAS/MAPK pathway - a major driver of colorectal carcinogenesis - on the circadian clock, we used a computational model which predicted that perturbation of BMAL1-mediated transcription can generate the circadian phenotypes similar to those observed in metastatic cell lines. Using an inducible RAS expression system, we show that overexpression of RAS disrupts the circadian clock and leads to an increase of the circadian period while RAS inhibition causes a shortening of period length, as predicted by our mathematical simulations. Together, our data demonstrate that perturbations induced by a single oncogene are sufficient to deregulate the mammalian circadian clock.
    Type of Publication: Journal article published
    PubMed ID: 24875049
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  • 4
    Abstract: Genetic heterogeneity between and within tumours is a major factor determining cancer progression and therapy response. Here we examined DNA sequence and DNA copy-number heterogeneity in colorectal cancer (CRC) by targeted high-depth sequencing of 100 most frequently altered genes. In 97 samples, with primary tumours and matched metastases from 27 patients, we observe inter-tumour concordance for coding mutations; in contrast, gene copy numbers are highly discordant between primary tumours and metastases as validated by fluorescent in situ hybridization. To further investigate intra-tumour heterogeneity, we dissected a single tumour into 68 spatially defined samples and sequenced them separately. We identify evenly distributed coding mutations in APC and TP53 in all tumour areas, yet highly variable gene copy numbers in numerous genes. 3D morpho-molecular reconstruction reveals two clusters with divergent copy number aberrations along the proximal-distal axis indicating that DNA copy number variations are a major source of tumour heterogeneity in CRC.
    Type of Publication: Journal article published
    PubMed ID: 28120820
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  • 5
    Abstract: Cancer cell lines (CCL) are important tools for cancer researchers world-wide. However, handling of cancer cell lines is error-prone, and critical errors such as misidentification and cross-contamination occur more often than acceptable. Based on the fact that CCL today very often are sequenced (partly or entirely) anyway as part of the studies performed, we developed Uniquorn, a computational method that reliably identifies CCL samples based on variant profiles derived from whole exome or whole genome sequencing. Notably, Uniquorn does neither require a particular sequencing technology nor downstream analysis pipeline but works robustly across different NGS platforms and analysis steps. We evaluated Uniquorn by comparing more than 1900 CCL profiles from three large CCL libraries, embracing 1585 duplicates, against each other. In this setting, our method achieves a sensitivity of 97% and specificity of 99%. Errors are strongly associated to low quality mutation profiles. The R-package Uniquorn is freely available as Bioconductor-package.
    Type of Publication: Journal article published
    PubMed ID: 28415721
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  • 6
    ISSN: 0378-1119
    Keywords: Epstein-Barr virus regulation ; Recombinant DNA ; immediate early promoters ; radioimmunoassay ; transient expression system
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Biology
    Type of Medium: Electronic Resource
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