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The development of in vitro technologies has produced new experimental information on protein binding onto DNA, which is accumulated in databases and used in studies of mechanisms regulating gene expression and in the development of computer-assisted methods of binding site recognition in pro- and eukaryotic genomes. However, it is still questionable to what extent in vitro selected sequences reflect the actual structures of the real transcription factor (TF) binding sites. The Kullback–Leibler divergence has been applied to the comparison of frequency matrices of TF binding sites constructed on sets of artificially selected sequences and real sites. The similarity of core sequences of real and artificial sites has been observed for 80% of all TFs studied. For 20% of TFs, in vitro selected binding site sequences have a broader range of permissible significant nucleotides not found in real sites. The optimal lengths of DNA sequences containing real binding sites, at which the sites are recognized most accurately, are estimated by the weight matrix method. For approximately 80% of the TFs studied, the optimal binding site length notably exceeds the lengths of the core sequences, as well as the lengths of in vitro selected sites. The detected features of in vitro selected TF binding sites impose constraints on their use in the development of computer-assisted methods of the recognition of candidate sites in genomic sequences.

Recognition of composite elements consisting of two transcription factor binding sites gets behind the studies of tissue-, stage- and condition-specific transcription. Genome-wide data on transcription factor binding generated with ChIP-seq method facilitate an identification of composite elements, but the existing bioinformatics tools either require ChIP-seq datasets for both partner transcription factors, or omit composite elements with motifs overlapping. Here we present an universal Motifs Co-Occurrence Tool (MCOT) that retrieves maximum information about overrepresented composite elements from a single ChIP-seq dataset. This includes homo- and heterotypic composite elements of four mutual orientations of motifs, separated with a spacer or overlapping, even if recognition of motifs within composite element requires various stringencies. Analysis of 52 ChIP-seq datasets for 18 human transcription factors confirmed that for over 60% of analyzed datasets and transcription factors predicted co-occurrence of motifs implied experimentally proven protein-protein interaction of respecting transcription factors. Analysis of 164 ChIP-seq datasets for 57 mammalian transcription factors showed that abundance of predicted composite elements with an overlap of motifs compared to those with a spacer more than doubled; and they had 1.5-fold increase of asymmetrical pairs of motifs with one more conservative ‘leading’ motif and another one ‘guided’.

Computer prediction of nucleosome positioning sites from DNA sequences is of great impor- tance for analyzing eukaryotic gene expression regulation. Investigation of experimentally found nucleosome positioning sites determined statistically significant contexts and revealed symmetry of their distribution about the center of a site. Internet-available software was developed to determine the profile of preference of genomic DNA for nucleosome formation (nucleosome potential) on the basis of Markov mod- els. A correlation of the nucleosome potential with the complexity of the nucleotide sequence text was es- tablished. The nucleosome potential was estimated for transcription factor binding sites, promoters, exons, and introns of eukaryotic genes. A difference in nucleosome potential between promoters of tissue-specific and constitutively expressed eukaryotic genes was shown. The software is available at the website of the In- stitute of Cytology and Genetics, Siberian Division, Russian Academy of Sciences at the address http://wwwmgs.bionet.nsc.ru/programs/VMM/.

The structure of the Transcription Regulatory Regions Database (TRRD) and the principles of describing transcription regulation of eukaryotic genes in TRRD are considered. Formalized description of the structural and functional organization of the regulatory gene regions is illustrated with examples. By now, TRRD is based on 3500 original works and contains data on transcription regulation of more than 1100 genes known to possess more than 5000 transcription factor binding sites and about 1600 regulatory elements (promoters, enhancers, silencers). TRRD is available at http://www.bionet.nsc.ru/trrd/

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.

Transcription Regulatory Regions Database (TRRD) has been developed for accumulation of experimental information on the structure–function features of regulatory regions of eukaryotic genes. Each entry in TRRD corresponds to a particular gene and contains a description of structure–function features of its regulatory regions (transcription factor binding sites, promoters, enhancers, silencers, etc.) and gene expression regulation patterns. The current release, TRRD 4.2.5, comprises the description of 760 genes, 3403 expression patterns, and >4600 regulatory elements including 3604 transcription factor binding sites, 600 promoters and 152 enhancers. This information was obtained through annotation of 2537 scientific publications. TRRD 4.2.5 is available through the WWW at http://wwwmgs.bionet.nsc.ru/mgs/dbases/trrd4/

The Transcription Regulatory Regions Database (TRRD) is a curated database designed for accumulation of experimental data on extended regulatory regions of eukaryotic genes, the regulatory elements they contain, i.e., transcription factor binding sites, promoters, enhancers, silencers, etc., and expression patterns of the genes. Release 4.1 of TRRD offers a number of significant improvements, in particular, a more detailed description of transcription factor binding sites, transcription factors per se, and gene expression patterns in a computer-readable format. In addition, the new TRRD release provides considerably more references to other molecular biological databases. TRRD 4.1 is installed under SRS and is available through the WWW at http://www.bionet.nsc.ru/trrd/

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/.

MOTIVATION: The goal of the work was to develop a WWW-oriented computer system providing a maximal integration of informational and software resources on the regulation of gene expression and navigation through them. Rapid growth of the variety and volume of information accumulated in the databases on regulation of gene expression necessarily requires the development of computer systems for automated discovery of the knowledge that can be further used for analysis of regulatory genomic sequences. RESULTS: The GeneExpress system developed includes the following major informational and software modules: (1) Transcription Regulation (TRRD) module, which contains the databases on transcription regulatory regions of eukaryotic genes and TRRD Viewer for data visualization; (2) Site Activity Prediction (ACTIVITY), the module for analysis of functional site activity and its prediction; (3) Site Recognition module, which comprises (a) B-DNA-VIDEO system for detecting the conformational and physicochemical properties of DNA sites significant for their recognition, (b) Consensus and Weight Matrices (ConsFrec) and (c) Transcription Factor Binding Sites Recognition (TFBSR) systems for detecting conservative contextual regions of functional sites and their recognition; (4) Gene Networks (GeneNet), which contains an object-oriented database accumulating the data on gene networks and signal transduction pathways, and the Java-based Viewer for exploration and visualization of the GeneNet information; (5) mRNA Translation (Leader mRNA), designed to analyze structural and contextual properties of mRNA 5'-untranslated regions (5'-UTRs) and predict their translation efficiency; (6) other program modules designed to study the structure-function organization of regulatory genomic sequences and regulatory proteins. AVAILABILITY: GeneExpress is available at http://wwwmgs.bionet.nsc. ru/systems/GeneExpress/ and the links to the mirror site(s) can be found at http://wwwmgs.bionet.nsc.ru/mgs/links/mirrors.html+ ++.

We have developed the Transcription Regulatory Regions Database (TRRD, http://www.bionet.nsc.ru/trrd/) designed for storage of data on the structural-functional organization of transcriptional regulatory regions of the eukaryotic genes and their expression patterns. TRRD contains experimentally supported data only. Knowledge extraction from scientific literature, storage and further application of the results are all stepwise, conforming to the Data Mining technology: i) knowledge extraction from scientific publications; ii) preprocessing (data cleaning, syntactic and semantic analysis; iii) data transformation; iv) application for prediction; v) interpretation of the obtained knowledge to resolve the timely issues in bioinformatics. TRRD contains a compilation of data on 2 344 genes, their 14 407 expression patterns, 3 490 regulatory units, and 10 135 transcription factor binding sites. TRRD is filled in by manual annotation of scientific publications. The information incorporated into TRRD is the result of annotations of 7 609 scientific papers. Sequence Retrieval System (SRS) is the main tool for search and navigation in TRRD. A large number of indexed fields in its SRS version allow the user to generate queries both within and between libraries. TRRD has thesauruses and search systems that provide additional options for data access. TRRD is currently linked to 20 worldwide information resources, including EMBL/GeneBank, Ensembl, EPD, SWISS-PROT, TRANSFAC, GDB, GeneCards, MGD, RGD, GO. The links serve as a framework for integration in a distributed network environment.

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/.