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52 Gonye et al.Currently, PAINT can process a list of gene identifiers (GenBank accessionnumbers, Clone IDs, Ensembl Gene IDs, and Entrez Gene IDs) to retrieve correspondingpromoter sequences and analyze the same for presence of TF-bindingsites. The tool then uses a statistical analysis, with or without gene expressionclustering results, to generate a set of candidate regulatory interactions and TF thatare likely to play a key role in the mechanisms underlying the cellular response.PAINT has been used in studying co-ordinated gene regulation in a wide range ofsystems including neuronal differentiation, neuronal adaptation, blood celldevelopment, retinal injury, brain stroke, and bladder inflammation (11–19).2. Materials1. Gene level identifier resources: the CloneUpdater tool for annotation updating andgene identifier conversion across different databases can be found at http://www.dbi.tju.edu/cloneupdater/html/template.php. The SOURCE tool for conversionbetween various gene identifiers can be found at http://source.stanford.edu. Ensemblgene identifiers can be obtained using the BioMart function at http://www.ensembl.org/Multi/martview.2. Gene list input data file: a user-provided single column list of gene identifiers, oneidentifier per line, in a plain text file. The data set and associated identifier list filesused in this article are a subset of the data described in ref. 11 and are available athttp://www.dbi.tju.edu/dbi/publications/MiMBchapter/.3. Cluster membership data file: a user-provided tab-delimited plain text file with twocolumns. The first column must contain one gene identifier per row and the secondcolumn must contain a corresponding single word alphanumeric cluster label. Anexample file is available in the online Supplemental Information at http://www.dbi.tju.edu/dbi/publications/MiMBchapter/.4. TF-binding site data: TRNA requires definitions of TF-binding sites call positionalweight matrices (PWM). PWMs for use with PAINT are provided in two formsfrom Biobase International Wolfenbüttel, Germany. A publicly available databaseof PWMs is accessed through http://www.gene-regulation.com. A professional andlicensed version is available from http://www.biobase-international.com/. PAINTrequires users to obtain an account with either of these resources if PAINT is tobe used for binding-site analysis. The professional version of TRANSFACBiobase International, Wolfenbüttel, Germany contains substantially higher numberof TREs and TF than the public version, and hence, the use of former significantlyimproves the TRNA.5. PAINT: the latest version of the PAINT is available at http://www.dbi.tju.edu/dbi/tools/paint/. The original version is described in ref. 11.2.1. PAINT ArchitectureThe modular architecture of PAINT, depicted in Fig. 1, is not organism specific.The key requirements are the availability of annotated genome sequence andinformation on TF-binding site motifs. PAINT 3.5 can conduct analysis specificto the human, mouse, and rat genomes. The tool contains five components: