54 research outputs found
Detecting Microsatellites in Genome Data: Variance in Definitions and Bioinformatic Approaches Cause Systematic Bias
Microsatellites are currently one of the most commonly used genetic markers. The application of bioinformatic tools has become common practice in the study of these short tandem repeats (STR). However, in silico studies can suffer from study bias. Using a meta-analysis on microsatellite distribution in yeast we show that estimates of numbers of repeats reported by different studies can differ in the order of several magnitudes, even within a single genome. These differences arise because varying definitions of microsatellites, spanning repeat size, array length and array composition, are used in different search paradigms, with minimum array length being the main influencing factor. Structural differences in the implemented search algorithm additionally contribute to variation in the number of repeats detected. We suggest that for future studies a consistent approach to STR searches is adopted in order to improve the power of intra- and interspecific comparison
Untersuchungen der Einsetzbarkeit von Smartphone-Applikationen zur Messung von Arbeitsumweltfaktoren am Beispiel Klima
Der Einsatz von Smartphones hat nicht nur im Alltag, sondern auch im industriellen Kontext in den letzten Jahren stark zugenommen. Die eingebaute Sensorik in Smartphones bietet Potential fĂŒr vielfĂ€ltige Anwendungen. Ein mögliches Einsatzgebiet stellt die Messung von Arbeitsumweltfaktoren wie LĂ€rm, Klima und Beleuchtung dar.
Hierzu wurde sich u.a. mit der Fragestellung beschĂ€ftigt, inwiefern mit Applikationen auf Smartphones arbeitswissenschaftliche Messungen des Arbeitsumweltfaktors Klima möglich sind. Im Ergebnis kann festgehalten werden, dass einzelne Applikationen fĂŒr orientierende Messungen herangezogen werden können. Zwischen verschiedenen Applikationen sind jedoch gröĂere Messabweichungen feststellbar. Dies bedingt eine geeignete Vorauswahl. Der nachfolgende Beitrag stellt ausgewĂ€hlte Ergebnisse der durchgefĂŒhrten Klimamessungen mittels Smartphones vor
Educational Fiscal Policy and Its Effects on How our Children Learn: Comparing Minnesota and Illinois
The study compares Illinoisâ and Minnesotaâs education fiscal policies. Illinois funds itâs education system mainly from the local level, whereas Minnesota funds itâs mainly from the state level. Thus, in Illinois, if there are discrepancies between household incomes in wealthier and poorer areas, the schools in wealthier areas would receive more money than those in poorer areas. Test scores are then compared. Illinois typically has lower scores than Minnesota. The conclusion is that Illinoisâ policies are hindering their studentsâ learning, compared to Minnesota students, with some mixed results
Refinement of computational identification of somatic copy number alterations using DNA methylation microarrays illustrated in cancers of unknown primary
High-throughput genomic technologies are increasingly used in personalized cancer medicine. However, computational tools to maximize the use of scarce tissues combining distinct molecular layers are needed. Here we present a refined strategy, based on the R-package 'conumee', to better predict somatic copy number alterations (SCNA) from deoxyribonucleic acid (DNA) methylation arrays. Our approach, termed hereafter as 'conumee-KCN', improves SCNA prediction by incorporating tumor purity and dynamic thresholding. We trained our algorithm using paired DNA methylation and SNP Array 6.0 data from The Cancer Genome Atlas samples and confirmed its performance in cancer cell lines. Most importantly, the application of our approach in cancers of unknown primary identified amplified potentially actionable targets that were experimentally validated by Fluorescence in situ hybridization and immunostaining, reaching 100% specificity and 93.3% sensitivity
Novel Targeting of DNA Methyltransferase Activity Inhibits Ewing Sarcoma Cell Proliferation and Enhances Tumor Cell Sensitivity to DNA Damaging Drugs by Activating the DNA Damage Response
DNA methylation is an important component of the epigenetic machinery that regulates the malignancy of Ewing sarcoma (EWS), the second most common primary bone tumor in children and adolescents. Coordination of DNA methylation and DNA replication is critical for maintaining epigenetic programming and the DNMT1 enzyme has been demonstrated to have an important role in both maintaining the epigenome and controlling cell cycle. Here, we showed that the novel nonnucleoside DNMT inhibitor (DNMTi) MC3343 induces a specific depletion of DNMT1 and affects EWS tumor proliferation through a mechanism that is independent on DNA methylation. Depletion of DNMT1 causes perturbation of the cell cycle, with an accumulation of cells in the G1 phase, and DNA damage, as revealed by the induction of gamma H2AX foci. These effects elicited activation of p53-dependent signaling and apoptosis in p53wt cells, while in p53 mutated cells, persistent micronuclei and increased DNA instability was observed. Treatment with MC3343 potentiates the efficacy of DNA damaging agents such as doxorubicin and PARP-inhibitors (PARPi). This effect correlates with increased DNA damage and synergistic tumor cytotoxicity, supporting the use of the DNMTi MC3343 as an adjuvant agent in treating EWS
A resilient formin-derived cortical actin meshwork in the rear drives actomyosin-based motility in 2D confinement
Cell migration is driven by the establishment of disparity between the cortical properties of the softer front and the more rigid rear allowing front extension and actomyosin-based rear contraction. However, how the cortical actin meshwork in the rear is generated remains elusive. Here we identify the mDia1-like formin A (ForA) from Dictyostelium discoideum that generates a subset of filaments as the basis of a resilient cortical actin sheath in the rear. Mechanical resistance of this actin compartment is accomplished by actin crosslinkers and IQGAP-related proteins, and is mandatory to withstand the increased contractile forces in response to mechanical stress by impeding unproductive blebbing in the rear, allowing efficient cell migration in two-dimensional-confined environments. Consistently, ForA supresses the formation of lateral protrusions, rapidly relocalizes to new prospective ends in repolarizing cells and is required for cortical integrity. Finally, we show that ForA utilizes the phosphoinositide gradients in polarized cells for subcellular targeting.Peer reviewe
Dynamics of Transcription Regulation in Human Bone Marrow Myeloid Differentiation to Mature Blood Neutrophils.
Neutrophils are short-lived blood cells that play a critical role in host defense against infections. To better comprehend neutrophil functions and their regulation, we provide a complete epigenetic overview, assessing important functional features of their differentiation stages from bone marrow-residing progenitors to mature circulating cells. Integration of chromatin modifications, methylation, and transcriptome dynamics reveals an enforced regulation of differentiation, for cellular functions such as release of proteases, respiratory burst, cell cycle regulation, and apoptosis. We observe an early establishment of the cytotoxic capability, while the signaling components that activate these antimicrobial mechanisms are transcribed at later stages, outside the bone marrow, thus preventing toxic effects in the bone marrow niche. Altogether, these data reveal how the developmental dynamics of the chromatin landscape orchestrate the daily production of a large number of neutrophils required for innate host defense and provide a comprehensive overview of differentiating human neutrophils
METTL1 promotes tumorigenesis through tRNA-derived fragment biogenesis in prostate cancer
Newly growing evidence highlights the essential role that epitranscriptomic marks play in the development of many cancers; however, little is known about the role and implications of altered epitranscriptome deposition in prostate cancer. Here, we show that the transfer RNA N-7-methylguanosine (m(7)G) transferase METTL1 is highly expressed in primary and advanced prostate tumours. Mechanistically, we find that METTL1 depletion causes the loss of m(7)G tRNA methylation and promotes the biogenesis of a novel class of small non-coding RNAs derived from 5'tRNA fragments. 5'tRNA-derived small RNAs steer translation control to favour the synthesis of key regulators of tumour growth suppression, interferon pathway, and immune effectors. Knockdown of Mettl1 in prostate cancer preclinical models increases intratumoural infiltration of pro-inflammatory immune cells and enhances responses to immunotherapy. Collectively, our findings reveal a therapeutically actionable role of METTL1-directed m(7)G tRNA methylation in cancer cell translation control and tumour biology
Genome-wide analysis of differential transcriptional and epigenetic variability across human immune cell types
Abstract
Background
A healthy immune system requires immune cells that adapt rapidly to environmental challenges. This phenotypic plasticity can be mediated by transcriptional and epigenetic variability.
Results
We apply a novel analytical approach to measure and compare transcriptional and epigenetic variability genome-wide across CD14+CD16â monocytes, CD66b+CD16+ neutrophils, and CD4+CD45RA+ naĂŻve T cells from the same 125 healthy individuals. We discover substantially increased variability in neutrophils compared to monocytes and T cells. In neutrophils, genes with hypervariable expression are found to be implicated in key immune pathways and are associated with cellular properties and environmental exposure. We also observe increased sex-specific gene expression differences in neutrophils. Neutrophil-specific DNA methylation hypervariable sites are enriched at dynamic chromatin regions and active enhancers.
Conclusions
Our data highlight the importance of transcriptional and epigenetic variability for the key role of neutrophils as the first responders to inflammatory stimuli. We provide a resource to enable further functional studies into the plasticity of immune cells, which can be accessed from:
http://blueprint-dev.bioinfo.cnio.es/WP10/hypervariability
Landscape of transcription in human cells
Eukaryotic cells make many types of primary and processed RNAs that are found either in specific sub-cellular compartments or throughout the cells. A complete catalogue of these RNAs is not yet available and their characteristic sub-cellular localizations are also poorly understood. Since RNA represents the direct output of the genetic information encoded by genomes and a significant proportion of a cellâs regulatory capabilities are focused on its synthesis, processing, transport, modifications and translation, the generation of such a catalogue is crucial for understanding genome function. Here we report evidence that three quarters of the human genome is capable of being transcribed, as well as observations about the range and levels of expression, localization, processing fates, regulatory regions and modifications of almost all currently annotated and thousands of previously unannotated RNAs. These observations taken together prompt to a redefinition of the concept of a gene
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