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

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

Bacteria-immunoglobulin-lymphocyte interactions--new aspects

Of 30 bacterial species tested 18 stimulated DNA synthesis in human blood lymphocytes. The maximum response was after 3-4 days of culture suggesting a mitogenic effect. This was confirmed by the induction of polyclonal antibody production shown by a plaque assay. Most bacterial species increased the DNA synthesis in B-enriched lymphocytes and unseparated lymphocytes but had negligible activity on T-enriched lymphocytes. Among bacteria with a mitogenic effect and ability to induce polyclonal antibody production are Staphylococcus aureus, Haemophilus influenzae, Mycobacterium tuberculosis, Neisseria gonorrhoeae, Streptococcus group A and Streptococcus pneumoniae. In an attempt to define structure (s) on the B-lymphocyte surface responsible for the lymphocyte stimulation the binding of IgD, IgM, and HLA-A, -B and HLA-D antigens to different bacterial species was investigated. A high IgD binding to N. catarrhalis and H. influenzae and a moderate binding of IgD to streptococci was found. Binding studies employing radiolabelled IgD Fab- and Fc-fragments indicated that the binding probably involves the CHl-region of the IgD molecule. Three purified radiolabelled myeloma IgM M-components were all shown to be efficiently bound to many bacteria indicating that a part of the IgM molecule other than the antigen-combining site can be involved in attachment to bacteria. Highly purified detergent-solubilized HLA-A, -B and HLA-D antigens, when separately incorporated into liposomes, were bound efficiently to two strains of N. catarrhalis and to one strain of H. influenzae weakly to one strain of E. coli, but not at all to another strain E. coli. Preliminary experiments indicate that these bacteria-immunoglobulin and bacteria-HLA-antigen interactions lead to lymphocyte stimulation