Bioinformatic interrogation of expression array data to identify nutritionally regulated genes potentially modulated by DNA methylation

DNA methylation occurs at CpG dinucleotide sites within the genome and is recognised as one of the mechanisms involved in regulation of gene expression. CpG sites are relatively underrepresented in the mammalian genome, but occur densely in regions called CpG islands (CGIs). CGIs located in the promoters of genes inhibit transcription when methylated by impeding transcription factor binding. Due to the malleable nature of DNA methylation, environmental factors are able to influence promoter CGI methylation patterns and thus influence gene expression. Recent studies have provided evidence that nutrition (and other environmental exposures) can cause altered CGI methylation but, with a few exceptions, the genes influenced by these exposures remain largely unknown. Here we describe a novel bioinformatics approach for the analysis of gene expression microarray data designed to identify regulatory sites within promoters of differentially expressed genes that may be influenced by changes in DNA methylation

Introducing WikiPathways as a Data-Source to Support Adverse Outcome Pathways for Regulatory Risk Assessment of Chemicals and Nanomaterials

A paradigm shift is taking place in risk assessment to replace animal models, reduce the number of economic resources, and refine the methodologies to test the growing number of chemicals and nanomaterials. Therefore, approaches such as transcriptomics, proteomics, and metabolomics have become valuable tools in toxicological research, and are finding their way into regulatory toxicity. One promising framework to bridge the gap between the molecular-level measurements and risk assessment is the concept of adverse outcome pathways (AOPs). These pathways comprise mechanistic knowledge and connect biological events from a molecular level toward an adverse effect outcome after exposure to a chemical. However, the implementation of omics-based approaches in the AOPs and their acceptance by the risk assessment community is still a challenge. Because the existing modules in the main repository for AOPs, the AOP Knowledge Base (AOP-KB), do not currently allow the integration of omics technologies, additional tools are required for omics-based data analysis and visualization. Here we show how WikiPathways can serve as a supportive tool to make omics data interoperable with the AOP-Wiki, part of the AOP-KB. Manual matching of key events (KEs) indicated that 67% could be linked with molecular pathways. Automatic connection through linkage of identifiers between the databases showed that only 30% of AOP-Wiki chemicals were found on WikiPathways. More loose linkage through gene names in KE and Key Event Relationships descriptions gave an overlap of 70 and 71%, respectively. This shows many opportunities to create more direct connections, for example with extended ontology annotations, improving its interoperability. This interoperability allows the needed integration of omics data linked to the molecular pathways with AOPs. A new AOP Portal on WikiPathways is presented to allow the community of AOP developers to collaborate and populate the molecular pathways that underlie the KEs of AOP-Wiki. We conclude that the integration of WikiPathways and AOP-Wiki will improve risk assessment because omics data will be linked directly to KEs and therefore allow the comprehensive understanding and description of AOPs. To make this assessment reproducible and valid, major changes are needed in both WikiPathways and AOP-Wiki

Answering biological questions: querying a systems biology database for nutrigenomics

The requirement of systems biology for connecting different levels of biological research leads directly to a need for integrating vast amounts of diverse information in general and of omics data in particular. The nutritional phenotype database addresses this challenge for nutrigenomics. A particularly urgent objective in coping with the data avalanche is making biologically meaningful information accessible to the researcher. This contribution describes how we intend to meet this objective with the nutritional phenotype database. We outline relevant parts of the system architecture, describe the kinds of data managed by it, and show how the system can support retrieval of biologically meaningful information by means of ontologies, full-text queries, and structured queries. Our contribution points out critical points, describes several technical hurdles. It demonstrates how pathway analysis can improve queries and comparisons for nutrition studies. Finally, three directions for future research are given

Mining Biological Pathways Using WikiPathways Web Services

WikiPathways is a platform for creating, updating, and sharing biological pathways [1]. Pathways can be edited and downloaded using the wiki-style website. Here we present a SOAP web service that provides programmatic access to WikiPathways that is complementary to the website. We describe the functionality that this web service offers and discuss several use cases in detail. Exposing WikiPathways through a web service opens up new ways of utilizing pathway information and assisting the community curation process

Systems Biology in ELIXIR: modelling in the spotlight

info:eu-repo/semantics/publishedVersio

Subcutaneous Adipose Tissue and Systemic Inflammation Are Associated With Peripheral but Not Hepatic Insulin Resistance in Humans

Obesity-related insulin resistance (IR) may develop in multiple organs, representing different etiologies towards cardiometabolic diseases. We identified abdominal subcutaneous adipose tissue (ScAT) transcriptome profiles in relation to liver or muscle IR by means of RNA sequencing in overweight/obese participants of the DiOGenes cohort (n=368). Tissue-specific IR phenotypes were derived from a 5-point oral glucose tolerance test. Hepatic and muscle IR were characterized by distinct abdominal ScAT transcriptome profiles. Genes related to extracellular remodeling were upregulated in individuals with primarily hepatic IR, whilst genes related to inflammation were upregulated in individuals with primarily muscle IR. In line with this, in two independent cohorts, CODAM (n=325) and the Maastricht Study (n=685), an increased systemic low-grade inflammation profile was specifically related to muscle IR, but not to liver IR. We propose that increased ScAT inflammatory gene expression may translate into an increased systemic inflammatory profile, linking ScAT inflammation to the muscle IR phenotype. These distinct IR phenotypes may provide leads for more personalized prevention of cardiometabolic diseases. DiOGenes was registered at clinicaltrials.gov as NCT00390637

Impact of exercise training on oxidative stress in individuals with a spinal cord injury

Individuals with a spinal cord injury (SCI) have an increased cardiovascular risk. We hypothesize that (anti)oxidative imbalance is associated with the increased cardiovascular risk in SCI, while exercise can reverse this status. The aim of the study is to compare baseline levels of oxidative stress and antioxidative capacity between individuals with SCI and able-bodied (AB) subjects, and to assess acute and long-term effects of functional electrical stimulation (FES) exercise on oxidative stress and antioxidative capacity in SCI. Venous blood was taken from subjects with an SCI (n = 9) and age- and gender-matched AB subjects (n = 9) to examine oxidative stress through malondialdehyde (MDA) levels, while superoxide dismutase (SOD) and glutathione peroxidase (GPx) enzyme levels represented anti-oxidative capacity. Subsequently, subjects with an SCI performed an 8-week FES exercise training period. Blood was taken before and after the first exercise bout and after the last FES session to examine the acute and chronic effect of FES exercise, respectively. Baseline levels of MDA, SOD and GPx were not different between individuals with SCI and AB subjects. SCI demonstrated a correlation between initial fitness level and MDA (R = −0.83, P = 0.05). MDA, SOD and GPx levels were neither altered by a single FES exercise bout nor by 8 weeks FES training. In conclusion, although individuals with an SCI demonstrate a preserved (anti)oxidative status, the correlation between fitness level and (anti)oxidative balance suggests that higher fitness levels are related to improved (anti)oxidative status in SCI. Nonetheless, the FES exercise stimulus was insufficient to acutely or chronically change (anti)oxidative status in individuals with an SCI