DNA methylation in glioblastoma: impact on gene expression and clinical outcome

International audienceBACKGROUND: Changes in promoter DNA methylation pattern of genes involved in key biological pathways have been reported in glioblastoma. Genome-wide assessments of DNA methylation levels are now required to decipher the epigenetic events involved in the aggressive phenotype of glioblastoma, and to guide new treatment strategies. RESULTS: We performed a whole-genome integrative analysis of methylation and gene expression profiles in 40 newly diagnosed glioblastoma patients. We also screened for associations between the level of methylation of CpG sites and overall survival in a cohort of 50 patients uniformly treated by surgery, radiotherapy and chemotherapy with concomitant and adjuvant temozolomide (STUPP protocol). The methylation analysis identified 616 CpG sites differentially methylated between glioblastoma and control brain, a quarter of which was differentially expressed in a concordant way. Thirteen of the genes with concordant CpG sites displayed an inverse correlation between promoter methylation and expression level in glioblastomas: B3GNT5, FABP7, ZNF217, BST2, OAS1, SLC13A5, GSTM5, ME1, UBXD3, TSPYL5, FAAH, C7orf13, and C3orf14. Survival analysis identified six CpG sites associated with overall survival. SOX10 promoter methylation status (two CpG sites) stratified patients similarly to MGMT status, but with a higher Area Under the Curve (0.78 vs. 0.71, p-value < 5e-04). The methylation status of the FNDC3B, TBX3, DGKI, and FSD1 promoters identified patients with MGMT-methylated tumors that did not respond to STUPP treatment (p-value < 1e-04). CONCLUSIONS: This study provides the first genome-wide integrative analysis of DNA methylation and gene expression profiles obtained from the same GBM cohort. We also present a methylome-based survival analysis for one of the largest uniformly treated GBM cohort ever studied, for more than 27,000 CpG sites. We have identified genes whose expression may be tightly regulated by epigenetic mechanisms and markers that may guide treatment decisions

HDAC Inhibition Decreases the Expression of EGFR in Colorectal Cancer Cells

Epidermal growth factor receptor (EGFR), a receptor tyrosine kinase which promotes cell proliferation and survival, is abnormally overexpressed in numerous tumors of epithelial origin, including colorectal cancer (CRC). EGFR monoclonal antibodies have been shown to increase the median survival and are approved for the treatment of colorectal cancer. Histone deacetylases (HDACs), frequently overexpressed in colorectal cancer and several malignancies, are another attractive targets for cancer therapy. Several inhibitors of HDACs (HDACi) are developed and exhibit powerful antitumor abilities. In this study, human colorectal cancer cells treated with HDACi exhibited reduced EGFR expression, thereby disturbed EGF-induced ERK and Akt phosphorylation. HDACi also decreased the expression of SGLT1, an active glucose transporter found to be stabilized by EGFR, and suppressed the glucose uptake of cancer cells. HDACi suppressed the transcription of EGFR and class I HDACs were proved to be involved in this event. Chromatin immunoprecipitation analysis showed that HDACi caused the dissociation of SP1, HDAC3 and CBP from EGFR promoter. Our data suggested that HDACi could serve as a single agent to block both EGFR and HDAC, and may bring more benefits to the development of CRC therapy

Open Babel: An open chemical toolbox

Background: A frequent problem in computational modeling is the interconversion of chemical structures between different formats. While standard interchange formats exist (for example, Chemical Markup Language) and de facto standards have arisen (for example, SMILES format), the need to interconvert formats is a continuing problem due to the multitude of different application areas for chemistry data, differences in the data stored by different formats (0D versus 3D, for example), and competition between software along with a lack of vendorneutral formats. Results: We discuss, for the first time, Open Babel, an open-source chemical toolbox that speaks the many languages of chemical data. Open Babel version 2.3 interconverts over 110 formats. The need to represent such a wide variety of chemical and molecular data requires a library that implements a wide range of cheminformatics algorithms, from partial charge assignment and aromaticity detection, to bond order perception and canonicalization. We detail the implementation of Open Babel, describe key advances in the 2.3 release, and outline a variety of uses both in terms of software products and scientific research, including applications far beyond simple format interconversion. Conclusions: Open Babel presents a solution to the proliferation of multiple chemical file formats. In addition, it provides a variety of useful utilities from conformer searching and 2D depiction, to filtering, batch conversion, and substructure and similarity searching. For developers, it can be used as a programming library to handle chemical data in areas such as organic chemistry, drug design, materials science, and computational chemistry. It is freely available under an open-source license fro

Differential Deployment of REST and CoREST Promotes Glial Subtype Specification and Oligodendrocyte Lineage Maturation

The repressor element-1 (RE1) silencing transcription factor/neuron-restrictive silencer factor (REST/NRSF) is a master transcriptional regulator that binds to numerous genomic RE1 sites where it acts as a molecular scaffold for dynamic recruitment of modulatory and epigenetic cofactors, including corepressor for element-1-silencing transcription factor (CoREST). CoREST also acts as a hub for various cofactors that play important roles in epigenetic remodeling and transcriptional regulation. While REST can recruit CoREST to its macromolecular complex, CoREST complexes also function at genomic sites independently of REST. REST and CoREST perform a broad array of context-specific functions, which include repression of neuronal differentiation genes in neural stem cells (NSCs) and other non-neuronal cells as well as promotion of neurogenesis. Despite their involvement in multiple aspects of neuronal development, REST and CoREST are not believed to have any direct modulatory roles in glial cell maturation.We challenged this view by performing the first study of REST and CoREST in NSC-mediated glial lineage specification and differentiation. Utilizing ChIP on chip (ChIP-chip) assays, we identified distinct but overlapping developmental stage-specific profiles for REST and CoREST target genes during astrocyte (AS) and oligodendrocyte (OL) lineage specification and OL lineage maturation and myelination, including many genes not previously implicated in glial cell biology or linked to REST and CoREST regulation. Amongst these factors are those implicated in macroglial (AS and OL) cell identity, maturation, and maintenance, such as members of key developmental signaling pathways and combinatorial transcription factor codes.Our results imply that REST and CoREST modulate not only neuronal but also glial lineage elaboration. These factors may therefore mediate critical developmental processes including the coupling of neurogenesis and gliogenesis and neuronal-glial interactions that underlie synaptic and neural network plasticity and homeostasis in health and in specific neurological disease states

Peopling mountain environments: Changing Andean livelihoods in north-west Argentina

Structural adjustment and neoliberal policy implementation in Latin America have had dramatic consequences for livelihoods and patterns of natural resource use in mountain regions. Restructuring of the agricultural economy has increased socio-economic hardship and reduced industrial labour requirements, altering traditional patterns of seasonal migration from these areas. This paper examines the implications of recent economic and political transformation for Andean livelihoods in the mountains of northwest Argentina. Case study material illustrates the local impacts of such changes on socio-economic dynamics, patterns of urban–rural interaction, and natural resource use. The research highlights the influence of agro-industrial restructuring, protected areas creation, and the distribution of social funds in the region. It reveals that local development is constrained and controlled not only by distant policies but also by contemporary local networks of political clientalism. The influence of both distant and proximate factors governing livelihoods and environmental impacts reinforces the value of geographical study in mountain areas, given its acute spatial and scalar awareness. The paper reaffirms the conception of mountain livelihoods as diverse and dynamic, shaped by economic, political, social and cultural factors as well as physical eality, and critiques the economic rationality of resource use assumed by policymakers and economic models

KDM1A microenvironment, its oncogenic potential, and therapeutic significance

The lysine-specific histone demethylase 1A (KDM1A) was the first demethylase to challenge the concept of the irreversible nature of methylation marks. KDM1A, containing a flavin adenine dinucleotide (FAD)-dependent amine oxidase domain, demethylates histone 3 lysine 4 and histone 3 lysine 9 (H3K4me1/2 and H3K9me1/2). It has emerged as an epigenetic developmental regulator and was shown to be involved in carcinogenesis. The functional diversity of KDM1A originates from its complex structure and interactions with transcription factors, promoters, enhancers, oncoproteins, and tumor-associated genes (tumor suppressors and activators). In this review, we discuss the microenvironment of KDM1A in cancer progression that enables this protein to activate or repress target gene expression, thus making it an important epigenetic modifier that regulates the growth and differentiation potential of cells. A detailed analysis of the mechanisms underlying the interactions between KDM1A and the associated complexes will help to improve our understanding of epigenetic regulation, which may enable the discovery of more effective anticancer drugs

Textilreste aus einem spätbronzezeitlichen Bergbaurevier bei Radfeld in Nordtirol – Sekundärnutzung von Stoffen zur Abdichtung

Im traditionsreichen Bergbaugebiet von Schwaz/Brixlegg im Nordtiroler Unterinntal fand während der späten Bronzezeit und frühen Eisenzeit ein umfangreicher Bergbau auf Kupfererze statt, der zahlreiche Spuren im Gelände hinterlassen hat. Montanarchäologische Forschungsprojekte der Universität Innsbruck, gefördert vom österreichischen Wissenschaftsfonds FWF und vom Tiroler Wissenschaftsfonds TWF, untersuchen seit den 1990er Jahren das prähistorische Montanwesen in diesem Raum. Zu den Forschungszielen gehören die Rekonstruktion der metallurgischen Produktionskette vom Erzabbau über die Aufbereitung bis hin zur Erzverhüttung und Gewinnung von Rohkupfer sowie der Arbeits- und Lebenswelt der prähistorischen Berg- und Hüttenleute. Die bislang prospektierten und in Ausschnitten archäologisch untersuchten Befunde belegen einen zeitlichen Schwerpunkt der Bergbauaktivitäten im 12. bis 8. Jh. v. Chr. Auf einem Verhüttungsplatz bei Radfeld (Mauk A) fanden sich 1997 bei der Freilegung einer „Waschrinne“ zur nassmechanischen Aufbereitung von Schlacken einige gut erhaltene Textilfragmente. Der archäologische Befund sowie die Textilfunde, Analysen zu Textiltechnik, Fasermaterial und Farbstoffen werden im folgenden Beitrag vorgestellt. Zudem werden die funktionelle Interpretation und kulturgeschichtliche Einordnung der Textilfunde diskutiert. -- Dans la célèbre région minière de Schwaz/Brixlegg en Tyrol (vallée de l’Inn) se trouvent de nombreuses traces de travaux miniers datant de l’Âge du Bronze final à l’Âge de Fer ancien. L’exploitation de l’époque se concentrait sur le cuivre gris, matière première locale pour la production du cuivre. Depuis 1993 des projets de recherches interdisciplinaires sont effectués à l`Université de Innsbruck sous la promotion du Wissenschaftsfonds autrichien (FWF) et tyrolien (TWF). Les objectifs de ces recherches comprennent la reconstruction de la chaîne opératoire pour la production du cuivre (extraction du minerai, traitement et métallurgie) aussi bien que du monde du travail et du cadre de vie des communautés de mineurs préhistoriques. La datation de ces activités tombe dans la période du 12ème au 8ème siècle av. J.-C. Une fouille archéologique sur un site de métallurgie extractive (Radfeld, Mauk A, 1997) a mis au jour les vestiges d’une installation de lavage où des scories de cuivre finement broyées ont été lavées pour récupérer des inclusions riches en cuivre. Dans ce contexte, quelques fragments de textile bien conservé ont pu être récupérés. Le textile, le matériau en lui-même, ses colorants et la technologie de sa production sont présentés et discutés dans cette contribution ainsi que l’interprétation fonctionnelle et le contexte (pré-)historique et culturel. -- In the traditional mining district Schwaz-Brixlegg in North-Tyrol a large amount of archaeological remains from an extensive Late Bronze Age and Early Iron Age copper ore mining is still visible in the landscape. In 1993 the University of Innsbruck started with mining archaeological investigations in this area in the frame of several research projects, supported by the Austrian Science Fund FWF and the Tyrolian Science Fund TWF. The aim of the research program is to identify and to date prehistoric mining activities and to reconstruct the metallurgical production chain including mining, beneficiation and smelting of copper ores. Also the working and living environment of the prehistoric miners and smelters is studied. So far evidence for mining activities from the 12th to the 8th century BC could be provided. In the frame of archaeological excavations in 1997 at the Late Bronze Age smelting site Mauk A near Radfeld a few well preserved textile fragments could be recovered in the context of a washing installation, where crushed slag had been processed in order to obtain concentrates of copper rich inclusions. In this paper the textile finds will be presented in their archaeological context together with analysis on textile techniques, seam materials and dyestuffs. Furthermore, their functional interpretation and positioning in a larger historical context will be discussed