Nucleic Acids Research Advance Access originally published online on October 30, 2008
Nucleic Acids Research 2009 37(Database issue):D61-D65; doi:10.1093/nar/gkn837
Nucleic Acids Research, 2009, Vol. 37, Database issue D61-D65
© 2008 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
PRODORIC (release 2009): a database and tool platform for the analysis of gene regulation in prokaryotes
Andreas Grote1,2,
Johannes Klein1,
Ida Retter1,
Isam Haddad1,
Susanne Behling1,
Boyke Bunk1,
Ilona Biegler1,
Svitlana Yarmolinetz1,
Dieter Jahn1,* and
Richard Münch1
1Institute of Microbiology, Technical University of Braunschweig, Spielmannstr. 7 and 2Institute of Bioinformatics and Biochemistry, Technical University of Braunschweig, Langer Kamp 19b, 38106 Braunschweig, Germany
*To whom correspondence should be addressed. Tel: +49 531 391 5801; Fax: +49 531 391 5854; Email: d.jahn{at}tu-bs.de
Received September 11, 2008. Accepted October 14, 2008.
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ABSTRACT
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PRODORIC is a database that provides annotated information on
the regulation of gene expression in prokaryotes. It integrates
a large compilation of gene regulatory data including transcription
factor binding sites, promoter structures and gene expression
patterns. The whole dataset is manually curated and relies on
published results extracted from the scientific literature.
The current extended version of PRODORIC contains gene regulatory
data for several new microorganisms. Major improvements were
realized in the design of the web interface and the accessibility
of the stored information. The database was further improved
by the implementation of various new tools for the elucidation
of gene regulatory interactions. Thus, the PRODORIC platform
represents a framework for the interactive exploration, prediction
and evaluation of gene regulatory networks in prokaryotes. PRODORIC
is accessible at
http://www.prodoric.de.
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INTRODUCTION
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In the last decade, the analysis and modeling of prokaryotic
gene regulatory networks as basis of a systems biology approach
to infection and biotechnological processes became of central
interest (
1,
2). In this context network reconstruction requires
reliable datasets of gene regulatory interactions, which are
usually only available in the scientific literature. The fast
accumulation of published gene regulatory data enhanced by the
availability of numerous finished genomes and by high-throughput
technologies fostered the development of structured repositories
in the form of public databases.
Several specialized gene regulation databases with focus on one model organism or several organism groups were established (3–8). The PRODORIC database was released in 2003 as a universal data source covering gene regulation in prokaryotes with focus on pathogenic bacteria (9). In a manual curation process relevant data is extracted by constantly screening of the scientific literature. The main part of PRODORIC contains a unique collection of transcription factor binding sites (TFBSs) and their interacting transcription factors. Besides these regulatory interactions, promoter structures with transcriptional initiation sites and sigma factor binding sites were included. Moreover, gene expression data derived from published microarray experiments were integrated. An integral part of PRODORIC are aligned profiles of TFBSs for a certain regulator represented as positions weight matrices (PWMs) and sequence logos (10,11). Provided PWMs are useful tools for pattern matching, and thus for the prediction of unknown putative TFBSs in DNA sequences of interest. For this purpose PRODORIC is associated with the prediction tool Virtual Footprint that allows a PWM based scanning of sequences or even whole genomes for new regulator targets (12).
Here, we summarize the modifications and improvements of PRODORIC made in the recent years. This comprises a significant increase of data content and updates of our tools. Moreover, PRODORIC was further developed towards a database and bioinformatics tool platform combining data and software for the interactive browsing, prediction and evaluation of gene regulatory networks in prokaryotes.
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DATABASE CURATION AND CONTENT
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PRODORIC relies completely on published results with experimental
validation and is not complemented with computational predicted
data. The transformation of free-text data from the primary
literature into structured information is constantly done manually
by a team of curators. During the process of literature screening
we observed that even refined PubMed searches with keywords
like ‘gene regulation’ and ‘prokaryotes’
are not sensitive enough since important classification terms
like ‘DNaseI footprint’ or ‘electromobility
shift assay’ are not generally part of PubMed abstracts.
Since these terms are often associated with figure captions
we optimized the literature preselection and data mining tasks
by use of the PDF search engine CaptionSearch (
13).
The main content of PRODORIC was significantly increased to an overall number of nearly 3000 TFBSs. The number of promoter and operon structures as well as expression profiles increased concurrently (Table 1). The main portion of regulatory interactions is expectedly covered by the two model organisms Escherichia coli and Bacillus subtilis. Interestingly, these are followed by Pseudomonas aeruginosa and Staphylococcus aureus revealing the relevance of data from pathogenic bacteria. An other striking group of bacteria annotated recently are phototrophic bacteria like Rhodobacter sphaeroides and Synechococcus sp. DNA sequence elements like TFBSs or transcriptional start sites are usually mapped to fixed genomic positions. Consequently, PRODORIC is limitted to sequenced organisms with elucidated genome sequence. Therefore, finished genomes are imported from flat files into PRODORIC in a frequent process, so the number of available organisms has increased to 696 different bacterial genomes with a total of 1304 replicons.
For the purpose of pattern matching and prediction of potentially
new transcription factor targets, a significant number of new
PWMs were generated from aligned profiles of TFBSs (
Figure 1).
This PWM library provides the data basis for the PRODORIC associated
prediction tool Virtual Footprint.
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DATABASE ACCESS
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There are principally four different ways to access PRODORIC:
- Submitting a database query via the supplied web forms.
- Browsing through the content by the use of genome browser GBpro.
- Exploring the regulatory network as visualized graph with the ProdoNet tool.
- Accessing the database via webservices [Simple Object Access Protocol (SOAP) interface].
The previously developed PRODORIC web interface was significantly improved with regard to its design, handling and web browser support. Database queries with genes, proteins, TFBSs and PWMs can be submitted via web forms. We added new sections for searching promoters, expression profiles and whole regulons. Besides the regular web forms, various improved possibilities for interactive browsing of the database contents were implemented. The new version of the genome browser GBpro offers an improved presentation of gene regulatory features both as genome map and formatted sequence. In this context, the application of inline frames enabled a more convenient browsing through the database contents. We recently developed ProdoNet, a new visualization tool for the exploration of PRODORIC contents in an interactive graph view (14). This tool enables the detection and visualization of underlying gene regulatory networks to uncover the multiple levels of gene regulation like regulatory circuits and various network motifs. Moreover, ProdoNet allows for the mapping and visualization of sets of co-expressed genes to gene regulatory network graphs. A different method to query the database without using the webpages was implemented recently via the establishment of webservices using SOAP. These webservices enable a platform-independent access to PRODORIC and offer an interactive way for data integration which was realized first for the SYSTOMONAS and ROSY platforms (15,16). A more detailed description of the SOAP interface and application examples are available on the PRODORIC website.
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PREDICTION OF GENE REGULATORY NETWORKS
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Although the PRODORIC core database excludes computationally
predicted data, we follow the approach of a database assisted
interactive prediction and validation of gene regulatory networks.
Produced results are usually most accurate since they are based
on the most recent set of data. For this purpose we developed
Virtual Footprint, a tool for the prediction of potentially
new transcription factor targets (
12). Various search patterns
can be defined by PWMs, IUPAC consensus strings or regular expressions.
Complex bipartite patterns consisting of two subpatterns separated
by a spacer are also possible. The integrated PWM library derived
from the PRODORIC dataset was extended to 197 patterns corresponding
to 163 different transcription factors (
Table 1). The Virtual
Footprint program allows the analysis of complete genomes with
one PWM, which is called ‘regulon analysis’. In
the other program mode ‘promoter analysis’, all
available patterns are applied on one sequence. The new PRODORIC
release 2009 was supplemented with a new tool called SMILE (similar
intergenic location analyzer). Using this novel tool, the evolutionary
conservation of Virtual Footprint matches can be further investigated
by a comparative analysis of orthologous promoter sequences
similar to a regulog analysis (
17). In SMILE both sequence and
positional conservation within an orthologous group of matches
can be analyzed. This approach enables the evaluation of putative
transcription factor targets and helps to rule out false-positive
predictions (
Figure 2).
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Figure 2. SMILE analysis using the Anr binding site in the promoter of the hemN gene. The results show both a high evolutional and positional conservation between the orthologous promoters (the list of matches was shortened).
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CONCLUSIONS
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PRODORIC is a manual curated data resource and bioinformatics
tool platform about gene regulation and gene expression covering
all sequenced prokaryotes. The whole system is supplemented
with various browsing, prediction and validation tools representing
a framework for the interactive analysis and visualization of
gene regulatory networks. The manual curation process of PRODORIC
will be continued. Mapping of gene regulatory interactions on
sequenced genomes will be one of the most challenging task.
The availability of reliable gene regulatoy networks will be
essential for modeling approaches in systems biology.
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FUNDING
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The Deutsche Forschungsgemeinschaft (Sonderforschungsbereich
578); German Bundesministerium für Bildung und Forschung
(ERA-NET grant 0313936C). Funding for open access publication
charge: Technical University of Braunschweig.
Conflict of interest statement. None declared.
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ACKNOWLEDGEMENTS
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We thank our database curators Anne-Kareen Blechert, Tobias
Knuuti and Roman Schubert for literature mining and trying to
keep track with numerous published results. We are grateful
to Karin and Lara Münch for assistance in web design. Finally,
we would like to thank Bernd Hoppe for excellent technical assistance
and financial management.
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Footnotes
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The authors wish it to be known that, in their opinion, the
first two authors should be regarded as joint First Authors
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