Alexander E. Kel

TRANSFAC®: transcriptional regulation, from patterns to profiles

The TRANSFAC database on eukaryotic transcriptional regulation, comprising data on transcription factors, their target genes and regulatory binding sites, has been extended and further developed, both in number of entries and in the scope and structure of the collected data. Structured fields for expression patterns have been introduced for transcription factors from human and mouse, using the CYTOMER database on anatomical structures and developmental stages. The functionality of Match, a tool for matrix-based search of transcription factor binding sites, has been enhanced. For instance, the program now comes along with a number of tissue-(or state-)specific profiles and new profiles can be created and modified with Match Profiler. The GENE table was extended and gained in importance, containing amongst others links to LocusLink, RefSeq and OMIM now. Further, (direct) links between factor and target gene on one hand and between gene and encoded factor on the other hand were introduced. The TRANSFAC public release is available at http://www.gene-regulation.com. For yeast an additional release including the latest data was made available separately as TRANSFAC Saccharomyces Module (TSM) at http://transfac.gbf.de. For CYTOMER free download versions are available at http://www.biobase.de:8080/index.html.

TRANSFAC® and its module TRANSCompel®: transcriptional gene regulation in eukaryotes

The TRANSFAC® database on transcription factors, their binding sites, nucleotide distribution matrices and regulated genes as well as the complementing database TRANSCompel® on composite elements have been further enhanced on various levels. A new web interface with different search options and integrated versions of Match™ and Patch™ provides increased functionality for TRANSFAC®. The list of databases which are linked to the common GENE table of TRANSFAC® and TRANSCompel® has been extended by: Ensembl, UniGene, EntrezGene, HumanPSD™ and TRANSPRO™. Standard gene names from HGNC, MGI and RGD, are included for human, mouse and rat genes, respectively. With the help of InterProScan, Pfam, SMART and PROSITE domains are assigned automatically to the protein sequences of the transcription factors. TRANSCompel® contains now, in addition to the COMPEL table, a separate table for detailed information on the experimental EVIDENCE on which the composite elements are based. Finally, for TRANSFAC®, in respect of data growth, in particular the gain of Drosophila transcription factor binding sites (by courtesy of the Drosophila DNase I footprint database) and of Arabidopsis factors (by courtesy of DATF, Database of Arabidopsis Transcription Factors) has to be stressed. The here described public releases, TRANSFAC® 7.0 and TRANSCompel® 7.0, are accessible under .

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

MATCHTM: a tool for searching transcription factor binding sites in DNA sequences

MatchTM is a weight matrix-based tool for searching putative transcription factor binding sites in DNA sequences. MatchTM is closely interconnected and distributed together with the TRANSFAC® database. In particular, MatchTM uses the matrix library collected in TRANSFAC® and therefore provides the possibility to search for a great variety of different transcription factor binding sites. Several sets of optimised matrix cut-off values are built in the system to provide a variety of search modes of different stringency. The user may construct and save his/her specific user profiles which are selected subsets of matrices including default or user-defined cut-off values. Furthermore a number of tissue-specific profiles are provided that were compiled by the TRANSFAC® team. A public version of the MatchTM tool is available at: http://www.gene-regulation.com/pub/programs.html#match. The same program with a different web interface can be found at http://compel.bionet.nsc.ru/Match/Match.html. An advanced version of the tool called MatchTM Professional is available at http://www.biobase.de.

Expanding the TRANSFAC database towards an expert system of regulatory molecular mechanisms

TRANSFAC is a database on transcription factors, their genomic binding sites and DNA-binding profiles. In addition to being updated and extended by new features, it has been complemented now by a series of additional database modules. Among them, modules which provide data about signal transduction pathways (TRANSPATH) or about cell types/organs/developmental stages (CYTOMER) are available as well as an updated version of the previously described COMPEL database. The databases are available on the WWW at http://transfac.gbf.de/

TRANSFAC, TRRD and COMPEL: towards a federated database system on transcriptional regulation

Three databases that provide data on transcriptional regulation are described. TRANSFAC is a database on transcription factors and their DNA binding sites. TRRD (Transcription Regulatory Region Database) collects information about complete regulatory regions, their regulation properties and architecture. COMPEL comprises specific information on composite regulatory elements. Here, we describe the present status of these databases and the first steps towards their federation.

Aberrant intestinal expression and allelic variants of mucin genes associated with inflammatory bowel disease

Loss of intestinal mucosa integrity is an important factor in the pathogenesis of inflammatory bowel disease (IBD). The aim of this study was to characterize expression changes and allelic variants of genes related to intestinal epithelial barrier function in this disease. Therefore, ileal and colonic mucosal biopsies from nonaffected regions of patients with ulcerative colitis (UC) and Crohn’s disease (CD), as well as non-IBD probands, were subjected to Affymetrix DNA-microarray analysis. Real-time reverse transcription polymerase chain reaction was used for verification in larger IBD sample numbers. Disturbed mRNA expression was identified for several mucin genes in both disease groups and tissues. A significant downregulation in the colon was obtained for MUC2 in CD and MUC12 in CD and UC. Expression analysis of all dysregulated mucins in a broad human tissue panel revealed dominant epithelial tissue-specific transcription. In silico analysis of the regulatory regions of these mucins indicated nuclear factor κB (NFκB) binding sites in each promoter. Furthermore, NFκB was overrepresented in mucin promoters and a component of a specific combination of transcription factors (composite module). In vivo stimulation experiments in the adenocarcinoma cell line LS174T showed inducible mucin expression by the cytokines tumor necrosis factor-α and transforming growth factor-β, which could be blocked by NFκB signaling inhibitors. Allelic discrimination screening obtained statistically significant associations for the MUC2–V116M (P = 0.003) polymorphism with CD and for MUC4–A585S (P = 0.025), as well as MUC13–R502S (P = 0.0003) with UC. These data suggest that the disturbed expression of mucin genes and the connection to the NFκB pathway may influence the integrity of the intestine and therefore contribute to the pathophysiology of IBD.

TRANSCompel®: a database on composite regulatory elements in eukaryotic genes

Originating from COMPEL, the TRANSCompel database emphasizes the key role of specific interactions between transcription factors binding to their target sites providing specific features of gene regulation in a particular cellular content. Composite regulatory elements contain two closely situated binding sites for distinct transcription factors and represent minimal functional units providing combinatorial transcriptional regulation. Both specific factor--DNA and factor--factor interactions contribute to the function of composite elements (CEs). Information about the structure of known CEs and specific gene regulation achieved through such CEs appears to be extremely useful for promoter prediction, for gene function prediction and for applied gene engineering as well. Each database entry corresponds to an individual CE within a particular gene and contains information about two binding sites, two corresponding transcription factors and experiments confirming cooperative action between transcription factors. The COMPEL database, equipped with the search and browse tools, is available at http://www.gene-regulation.com/pub/databases.html#transcompel. Moreover, we have developed the program CATCH for searching potential CEs in DNA sequences. It is freely available as CompelPatternSearch at http://compel.bionet.nsc.ru/FunSite/CompelPatternSearch.html.

Bifurcation analysis of the regulatory modules of the mammalian G1/S transition

MOTIVATION Mathematical models of the cell cycle can contribute to an understanding of its basic mechanisms. Modern simulation tools make the analysis of key components and their interactions very effective. This paper focuses on the role of small modules and feedbacks in the gene-protein network governing the G1/S transition in mammalian cells. Mutations in this network may lead to uncontrolled cell proliferation. Bifurcation analysis helps to identify the key components of this extremely complex interaction network. RESULTS We identify various positive and negative feedback loops in the network controlling the G1/S transition. It is shown that the positive feedback regulation of E2F1 and a double activator-inhibitor module can lead to bistability. Extensions of the core module preserve the essential features such as bistability. The complete model exhibits a transcritical bifurcation in addition to bistability. We relate these bifurcations to the cell cycle checkpoint and the G1/S phase transition point. Thus, core modules can explain major features of the complex G1/S network and have a robust decision taking function.

Eukaryotic mRNAs encoding abundant and scarce proteins are statistically dissimilar in many structural features.

It is well known that non‐coding mRNA sequences are dissimilar in many structural features. For individual mRNAs correlations were found for some of these features and their translational efficiency. However, no systematic statistical analysis was undertaken to relate protein abundance and structural characteristics of mRNA encoding the given protein. We have demonstrated that structural and contextual features of eukaryotic mRNAs encoding high‐ and low‐abundant proteins differ in the 5′ untranslated regions (UTR). Statistically, 5′ UTRs of low‐expression mRNAs are longer, their guanine plus cytosine content is higher, they have a less optimal context of the translation initiation codons of the main open reading frames and contain more frequently upstream AUG than 5′ UTRs of high‐expression mRNAs. Apart from the differences in 5′ UTRs, high‐expression mRNAs contain stronger termination signals. Structural features of low‐ and high‐expression mRNAs are likely to contribute to the yield of their protein products.