Gilberto Fragoso

The MGED Ontology: a resource for semantics-based description of microarray experiments

MOTIVATION The generation of large amounts of microarray data and the need to share these data bring challenges for both data management and annotation and highlights the need for standards. MIAME specifies the minimum information needed to describe a microarray experiment and the Microarray Gene Expression Object Model (MAGE-OM) and resulting MAGE-ML provide a mechanism to standardize data representation for data exchange, however a common terminology for data annotation is needed to support these standards. RESULTS Here we describe the MGED Ontology (MO) developed by the Ontology Working Group of the Microarray Gene Expression Data (MGED) Society. The MO provides terms for annotating all aspects of a microarray experiment from the design of the experiment and array layout, through to the preparation of the biological sample and the protocols used to hybridize the RNA and analyze the data. The MO was developed to provide terms for annotating experiments in line with the MIAME guidelines, i.e. to provide the semantics to describe a microarray experiment according to the concepts specified in MIAME. The MO does not attempt to incorporate terms from existing ontologies, e.g. those that deal with anatomical parts or developmental stages terms, but provides a framework to reference terms in other ontologies and therefore facilitates the use of ontologies in microarray data annotation. AVAILABILITY The MGED Ontology version.1.2.0 is available as a file in both DAML and OWL formats at http://mged.sourceforge.net/ontologies/index.php. Release notes and annotation examples are provided. The MO is also provided via the NCICBs Enterprise Vocabulary System (http://nciterms.nci.nih.gov/NCIBrowser/Dictionary.do). CONTACT Stoeckrt@pcbi.upenn.edu SUPPLEMENTARY INFORMATION Supplementary data are available at Bioinformatics online.

The National Cancer Institute's thésaurus and ontology

The NCI Thysaurus is a public domain description logic-based terminology produced by the National Cancer Institute, and distributed as a component of the NCI Center for Bioinformatics caCORE distribution. It is deep and complex compared to most broad clinical vocabularies, implementing rich semantic interrelationships between the nodes of its taxonomies. The semantic relationships in the Thysaurus are intended to facilitate translational research and to support the bioinformatics infrastructure of the Institute.

caCORE: A common infrastructure for cancer informatics

MOTIVATION Sites with substantive bioinformatics operations are challenged to build data processing and delivery infrastructure that provides reliable access and enables data integration. Locally generated data must be processed and stored such that relationships to external data sources can be presented. Consistency and comparability across data sets requires annotation with controlled vocabularies and, further, metadata standards for data representation. Programmatic access to the processed data should be supported to ensure the maximum possible value is extracted. Confronted with these challenges at the National Cancer Institute Center for Bioinformatics, we decided to develop a robust infrastructure for data management and integration that supports advanced biomedical applications. RESULTS We have developed an interconnected set of software and services called caCORE. Enterprise Vocabulary Services (EVS) provide controlled vocabulary, dictionary and thesaurus services. The Cancer Data Standards Repository (caDSR) provides a metadata registry for common data elements. Cancer Bioinformatics Infrastructure Objects (caBIO) implements an object-oriented model of the biomedical domain and provides Java, Simple Object Access Protocol and HTTP-XML application programming interfaces. caCORE has been used to develop scientific applications that bring together data from distinct genomic and clinical science sources. AVAILABILITY caCORE downloads and web interfaces can be accessed from links on the caCORE web site (http://ncicb.nci.nih.gov/core). caBIO software is distributed under an open source license that permits unrestricted academic and commercial use. Vocabulary and metadata content in the EVS and caDSR, respectively, is similarly unrestricted, and is available through web applications and FTP downloads. SUPPLEMENTARY INFORMATION http://ncicb.nci.nih.gov/core/publications contains links to the caBIO 1.0 class diagram and the caCORE 1.0 Technical Guide, which provide detailed information on the present caCORE architecture, data sources and APIs. Updated information appears on a regular basis on the caCORE web site (http://ncicb.nci.nih.gov/core).

caCORE version 3: Implementation of a model driven, service-oriented architecture for semantic interoperability

One of the requirements for a federated information system is interoperability, the ability of one computer system to access and use the resources of another system. This feature is particularly important in biomedical research systems, which need to coordinate a variety of disparate types of data. In order to meet this need, the National Cancer Institute Center for Bioinformatics (NCICB) has created the cancer Common Ontologic Representation Environment (caCORE), an interoperability infrastructure based on Model Driven Architecture. The caCORE infrastructure provides a mechanism to create interoperable biomedical information systems. Systems built using the caCORE paradigm address both aspects of interoperability: the ability to access data (syntactic interoperability) and understand the data once retrieved (semantic interoperability). This infrastructure consists of an integrated set of three major components: a controlled terminology service (Enterprise Vocabulary Services), a standards-based metadata repository (the cancer Data Standards Repository) and an information system with an Application Programming Interface (API) based on Domain Model Driven Architecture. This infrastructure is being leveraged to create a Semantic Service-Oriented Architecture (SSOA) for cancer research by the National Cancer Institutes cancer Biomedical Informatics Grid (caBIG).

Characterization of BCE-1, a Transcriptional Enhancer Regulated by Prolactin and Extracellular Matrix and Modulated by the State of Histone Acetylation

ABSTRACT We have previously described a 160-bp enhancer (BCE-1) in the bovine β-casein gene that is activated in the presence of prolactin and extracellular matrix (ECM). Here we report the characterization of the enhancer by deletion and site-directed mutagenesis, electrophoretic mobility shift analysis, and in vivo footprinting. Two essential regions were identified by analysis of mutant constructions: one binds C/EBP-β and the other binds MGF/STAT5 and an as-yet-unidentified binding protein. However, no qualitative or quantitative differences in the binding of these proteins were observed in electrophoretic mobility shift analysis using nuclear extracts derived from cells cultured in the presence or absence of ECM with or without prolactin, indicating that prolactin- and ECM-induced transcription was not dependent on the availability of these factors in the functional cell lines employed. An in vivo footprinting analysis of the factors bound to nuclear chromatin in the presence or absence of ECM and/or prolactin found no differences in the binding of C/EBP-β but did not provide definitive results for the other factors. Neither ECM nor prolactin activated BCE-1 in transient transfections, suggesting that the chromosomal structure of the integrated template may be required for ECM-induced transcription. Further evidence is that treatment of cells with inhibitors of histone deacetylase was sufficient to induce transcription of integrated BCE-1 in the absence of ECM. Together, these results suggest that the ECM induces a complex interaction between the enhancer-bound transcription factors, the basal transcriptional machinery, and a chromosomally integrated template responsive to the acetylation state of the histones.

Modeling a description logic vocabulary for cancer research

The National Cancer Institute has developed the NCI Thesaurus, a biomedical vocabulary for cancer research, covering terminology across a wide range of cancer research domains. A major design goal of the NCI Thesaurus is to facilitate translational research. We describe: the features of Ontylog, a description logic used to build NCI Thesaurus; our methodology for enhancing the terminology through collaboration between ontologists and domain experts, and for addressing certain real world challenges arising in modeling the Thesaurus; and finally, we describe the conversion of NCI Thesaurus from Ontylog into Web Ontology Language Lite. Ontylog has proven well suited for constructing big biomedical vocabularies. We have capitalized on the Ontylog constructs Kind and Role in the collaboration process described in this paper to facilitate communication between ontologists and domain experts. The artifacts and processes developed by NCI for collaboration may be useful in other biomedical terminology development efforts.

Structure and Dynamic Properties of a Glucocorticoid Receptor-Induced Chromatin Transition

ABSTRACT Activation of the mouse mammary tumor virus (MMTV) promoter by the glucocorticoid receptor (GR) is associated with a chromatin structural transition in the B nucleosome region of the viral long terminal repeat (LTR). Recent evidence indicates that this transition extends upstream of the B nucleosome, encompassing a region larger than a single nucleosome (G. Fragoso, W. D. Pennie, S. John, and G. L. Hager, Mol. Cell. Biol. 18:3633–3644). We have reconstituted MMTV LTR DNA into a polynucleosome array using Drosophila embryo extracts. We show binding of purified GR to specific GR elements within a large, multinucleosome array and describe a GR-induced nucleoprotein transition that is dependent on ATP and a HeLa nuclear extract. Previously uncharacterized GR binding sites in the upstream C nucleosome region are involved in the extended region of chromatin remodeling. We also show that GR-dependent chromatin remodeling is a multistep process; in the absence of ATP, GR binds to multiple sites on the chromatin array and prevents restriction enzyme access to recognition sites. Upon addition of ATP, GR induces remodeling and a large increase in access to enzymes sites within the transition region. These findings suggest a dynamic model in which GR first binds to chromatin after ligand activation, recruits a remodeling activity, and is then lost from the template. This model is consistent with the recent description of a “hit-and-run” mechanism for GR action in living cells (J. G. McNally, W. G. Müller, D. Walker, and G. L. Hager, Science 287:1262–1264, 2000).

Overview and Utilization of the NCI Thesaurus

The NCI Thesaurus is a reference terminology covering areas of basic and clinical science, built with the goal of facilitating translational research in cancer. It contains nearly 110 000 terms in approximately 36000 concepts, partitioned in 20 subdomains, which include diseases, drugs, anatomy, genes, gene products, techniques, and biological processes, among others, all with a cancer-centric focus in content, and originally designed to support coding activities across the National Cancer Institute. Each concept represents a unit of meaning and contains a number of annotations, such as synonyms and preferred name, as well as annotations such as textual definitions and optional references to external authorities. In addition, concepts are modelled with description logic (DL) and defined by their relationships to other concepts; there are currently approximately 90 types of named relations declared in the terminology. The NCI Thesaurus is produced by the Enterprise Vocabulary Services project, a collaborative effort between the NCI Center for Bioinformatics and the NCI Office of Communications, and is part of the caCORE infrastructure stack (http://ncicb.nci.nih.gov/NCICB/core). It can be accessed programmatically through the open caBIO API and browsed via the web (http://nciterms.nci.nih.gov). A history of editing changes is also accessible through the API. In addition, the Thesaurus is available for download in various file formats, including OWL, the web ontology language, to facilitate its utilization by others.

The Position and Length of the Steroid-Dependent Hypersensitive Region in the Mouse Mammary Tumor Virus Long Terminal Repeat Are Invariant despite Multiple Nucleosome B Frames

ABSTRACT Stimulation of the mouse mammary tumor virus with steroids results in the generation of a DNase I-hypersensitive region (HSR) spanning the hormone responsive element (HRE) in the long terminal repeat. Restriction enzymes were used to characterize the accessibility of various sites within the HSR of mouse mammary tumor virus long terminal repeat-reporter constructions in four different cell lines. The glucocorticoid-dependent HSR was found to span minimally 187 bases, a stretch of DNA longer than that associated with histones in the core particle. Although the 5′-most receptor binding site within the HRE is downstream of −190, hypersensitive sites were found further upstream to at least −295. The relationship in the accessibility between pairs of sites in the vicinity of the HSR was further examined in one cell line by a two-enzyme restriction access assay. In the uninduced state, the accessibilities at these sites were found to be independent of each other. In contrast, when stimulated with hormone, the accessibilities at these sites were observed to become linked. That is, once a distinct promoter was activated, all of the sites within the HSR of that molecule became accessible. The HSR formed along an invariant stretch of DNA sequence despite the multiplicity of nucleosome frames in the nucleosome B region, where the HRE is located. The results indicate that the macroscopic length of the HSR does not arise from core length-remodeling events in molecules containing Nuc-B in alternative positions.

The Ontology for Biomedical Investigations

The Ontology for Biomedical Investigations (OBI) is an ontology that provides terms with precisely defined meanings to describe all aspects of how investigations in the biological and medical domains are conducted. OBI re-uses ontologies that provide a representation of biomedical knowledge from the Open Biological and Biomedical Ontologies (OBO) project and adds the ability to describe how this knowledge was derived. We here describe the state of OBI and several applications that are using it, such as adding semantic expressivity to existing databases, building data entry forms, and enabling interoperability between knowledge resources. OBI covers all phases of the investigation process, such as planning, execution and reporting. It represents information and material entities that participate in these processes, as well as roles and functions. Prior to OBI, it was not possible to use a single internally consistent resource that could be applied to multiple types of experiments for these applications. OBI has made this possible by creating terms for entities involved in biological and medical investigations and by importing parts of other biomedical ontologies such as GO, Chemical Entities of Biological Interest (ChEBI) and Phenotype Attribute and Trait Ontology (PATO) without altering their meaning. OBI is being used in a wide range of projects covering genomics, multi-omics, immunology, and catalogs of services. OBI has also spawned other ontologies (Information Artifact Ontology) and methods for importing parts of ontologies (Minimum information to reference an external ontology term (MIREOT)). The OBI project is an open cross-disciplinary collaborative effort, encompassing multiple research communities from around the globe. To date, OBI has created 2366 classes and 40 relations along with textual and formal definitions. The OBI Consortium maintains a web resource (http://obi-ontology.org) providing details on the people, policies, and issues being addressed in association with OBI. The current release of OBI is available at http://purl.obolibrary.org/obo/obi.owl.