O. A. Podkolodnaya

Databases on transcriptional regulation: TRANSFAC, TRRD and COMPEL

TRANSFAC, TRRD (Transcription Regulatory Region Database) and COMPEL are databases which store information about transcriptional regulation in eukaryotic cells. The three databases provide distinct views on the components involved in transcription: transcription factors and their binding sites and binding profiles (TRANSFAC), the regulatory hierarchy of whole genes (TRRD), and the structural and functional properties of composite elements (COMPEL). The quantitative and qualitative changes of all three databases and connected programs are described. The databases are accessible via WWW:http://transfac.gbf.de/TRANSFAC orhttp://www.bionet.nsc.ru/TRRD

Transcription Regulatory Regions Database (TRRD): its status in 2002

Transcription Regulatory Regions Database (TRRD) is an informational resource containing an integrated description of the gene transcription regulation. An entry of the database corresponds to a gene and contains the data on localization and functions of the transcription regulatory regions as well as gene expression patterns. TRRD contains only experimental data that are inputted into the database through annotating scientific publication. TRRD release 6.0 comprises the information on 1167 genes, 5537 transcription factor binding sites, 1714 regulatory regions, 14 locus control regions and 5335 expression patterns obtained through annotating 3898 scientific papers. This information is arranged in seven databases: TRRDGENES (general gene description), TRRDLCR (locus control regions); TRRDUNITS (regulatory regions: promoters, enhancers, silencers, etc.), TRRDSITES (transcription factor binding sites), TRRDFACTORS (transcription factors), TRRDEXP (expression patterns) and TRRDBIB (experimental publications). Sequence Retrieval System (SRS) is used as a basic tool for navigating and searching TRRD and integrating it with external informational and software resources. The visualization tool, TRRD Viewer, provides the information representation in a form of maps of gene regulatory regions. The option allowing nucleotide sequences to be searched for according to their homology using BLAST is also included. TRRD is available at http://www.bionet.nsc.ru/trrd/.

GeneNet in 2005

The GeneNet system is designed for collection and analysis of the data on gene and metabolic networks, signal transduction pathways and kinetic characteristics of elementary processes. In the past 2 years, the GeneNet structure was considerably improved: (i) the current version of the database is now implemented using ORACLE9i; (ii) the capacities to describe the structure of the protein complexes and the interactions between the units are increased; (iii) two tables with kinetic constants and more detailed descriptions of certain reactions were added; and (iv) a module for kinetic modeling was supplemented. The current SRS release of the GeneNet database contains 37 graphical maps of gene networks, as well as descriptions of 1766 proteins, 1006 genes, 241 small molecules and 3254 relationships between gene network units, and 552 kinetic constants. Information distributed between 16 interlinked tables was obtained by annotating 1980 journal publications. SRS release of the GeneNet database, the graphical viewer and the modeling section are available at http://wwwmgs.bionet.nsc.ru/mgs/gnw/genenet/.

Oligonucleotide frequency matrices addressed to recognizing functional DNA sites.

MOTIVATION Recognition of functional sites remains a key event in the course of genomic DNA annotation. It is well known that a number of sites have their own specific oligonucleotide content. This pinpoints the fact that the preference of the site-specific nucleotide combinations at adjacent positions within an analyzed functional site could be informative for this site recognition. Hence, Web-available resources describing the site-specific oligonucleotide content of the functional DNA sites and applying the above approach for site recognition are needed. However, they have been poorly developed up to now. RESULTS To describe the specific oligonucleotide content of the functional DNA sites, we introduce the oligonucleotide alphabets, out of which the frequency matrix for a given site could be constructed in addition to a traditional nucleotide frequency matrix. Thus, site recognition accuracy increases. This approach was implemented in the activated MATRIX database accumulating oligonucleotide frequency matrices of the functional DNA sites. We have demonstrated that the false-positive error of the functional site recognition decreases if the oligonucleotide frequency matrixes are added to the nucleotide frequency matrixes commonly used. AVAILABILITY The MATRIX database is available on the Web, http://wwwmgs.bionet.nsc.ru/Dbases/MATRIX/ and the mirror site, http://www.cbil.upenn.edu/mgs/systems/c onsfreq/.

GeneNet: a database on structure and functional organisation of gene networks.

The GeneNet database is designed for accumulation of information on gene networks. Original technology applied in GeneNet enables description of not only a gene network structure and functional relationships between components, but also metabolic and signal transduction pathways. Specialised software, GeneNet Viewer, automatically displays the graphical diagram of gene networks described in the database. Current release 3.0 of GeneNet database contains descriptions of 25 gene networks, 945 proteins, 567 genes, 151 other substances and 1364 relationships between components of gene networks. Information distributed between 14 interlinked tables was obtained by annotating 968 scientific publications. The SRS-version of GeneNet database is freely available (http://wwwmgs.bionet.nsc.ru/mgs/systems/genenet/).

Artsite Database: Comparison of In Vitro Selected and Natural Binding Sites of Eukaryotic Transcription Factors

The ArtSite database was developed; the database compiles the information on the structures of eukaryotic transcription factor binding sites and/or their DNA-binding domains obtained from in vitro selected sequences. Current release of the database comprises 420 matrices describing specific features of binding sites or their DNA-binding domains for over 200 transcription factors. The matrices were constructed basing on alignments of representative samples of transcription factor binding sites, totally containing over 10 thousand sequences.

Generalized Chemokinetic Method for Gene Network Simulation

Development of methods for mathematical simulation of biological systems and building specific simulations is an important trend of bioinformatics. Here we describe the method of generalized chemokinetic simulation generating flexible and adequate simulations of various biological systems. Adequate simulations of complex nonlinear gene networks—control system of cholesterol by synthesis in the cell and erythrocyte differentiation and maturation—are given as examples. The simulations were expressed in terms of unit processes—biochemical reactions. Optimal sets of parameters were determined and the systems were numerically simulated under various conditions. The simulations allow us to study the possible functional conditions of these gene networks, calculate the consequences of mutations, and define optimal strategies for their correction including therapeutic ones. A graphical user interface for these simulations is available at http://wwwmgs.bionet.nsc.ru/systems/MGL/GeneNet/

Candidate SNP Markers of Chronopathologies Are Predicted by a Significant Change in the Affinity of TATA-Binding Protein for Human Gene Promoters

Variations in human genome (e.g., single nucleotide polymorphisms, SNPs) may be associated with hereditary diseases, their complications, comorbidities, and drug responses. Using Web service SNP_TATA_Comparator presented in our previous paper, here we analyzed immediate surroundings of known SNP markers of diseases and identified several candidate SNP markers that can significantly change the affinity of TATA-binding protein for human gene promoters, with circadian consequences. For example, rs572527200 may be related to asthma, where symptoms are circadian (worse at night), and rs367732974 may be associated with heart attacks that are characterized by a circadian preference (early morning). By the same method, we analyzed the 90 bp proximal promoter region of each protein-coding transcript of each human gene of the circadian clock core. This analysis yielded 53 candidate SNP markers, such as rs181985043 (susceptibility to acute Q fever in male patients), rs192518038 (higher risk of a heart attack in patients with diabetes), and rs374778785 (emphysema and lung cancer in smokers). If they are properly validated according to clinical standards, these candidate SNP markers may turn out to be useful for physicians (to select optimal treatment for each patient) and for the general population (to choose a lifestyle preventing possible circadian complications of diseases).

Transcription Regulatory Regions Database (TRRD): A Source of Experimentally Confirmed Data on Transcription Regulatory Regions of Eukaryotic Genes

The goal of creation of the Transcription Regulatory Regions Database (TRRD) was to provide a complete and adequate description of the structure-function organization of transcription regulatory regions in eukaryotic genes. TRRD contains only experimentally confirmed data about (i) transcription factor binding sites; (ii) regulatory units (promoter regions, enhancers, and silencers); and (iii) locus control regions. The main tool for searching TRRD and navigation in it is SRS. TRRD has hierarchically organized vocabularies and thesauruses used for developing specialized data retrieval tools. The current TRRD release contains information about 2308 eukaryotic genes (of them, 34 % are human genes) inputted basing on annotation of 7565 scientific papers. For these genes, the largest in the world sets of experimentally confirmed regulatory units (3439) and transcription factor binding sites (10 045) are collected in TRRD. Of them, 37 % of regulatory units and 38 % of binding sites are related to human genes. This paper characterizes groups of experiments basing on which regulatory units and binding sites are annotated. Examples of TRRD entries are given. The database is available at http://www.bionet.nsc.ru/trrd/.

Comparative Analysis of Methods Recognizing Potential Transcription Factor Binding Sites

A complex approach to recognition of transcription factor binding sites (TFBS) has been developed, based on four methods: (i) weight matrix, (ii) information content, (iii) multidimensional alignment, and (iv) pairwise alignment with the most similar representative of known sites. It has been shown that none of the methods considered is optimal for all kinds of sites, so in each case the appropriate way of recognition should be chosen. The approach proposed allows one to minimize the errors in TFBS recognition. The program available through the Internet (http://www.sgi.sscc.ru/mgs/programs/multalig/) has been created to search for the potential TFBS in nucleotide sequences set by the user.