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

TRANSCompel®: a database on composite regulatory elements in eukaryotic genes 332–334 Nucleic Acids Research, 2002, Vol. 30, No. 1 © 2002 Oxford University Press TRANSCompel : a database on composite regulatory elements in eukaryotic genes 1,2, 1,2 1 2 Olga V. Kel-Margoulis *, Alexander E. Kel , Ingmar Reuter , Igor V. Deineko and 1,3 Edgar Wingender 1 2 BIOBASE GmbH, Halchtersche Strasse 33, D-38304 Wolfenbüttel, Germany, Institute of Cytology and Genetics SB RAN, 10 Lavrentyev pr., 630090, Novosibirsk, Russia and AG Bioinformatik, Gesellschaft für Biotechnologische Forschung mbH, Mascheroder Weg 1, D-38124 Braunschweig, Germany Received September 24, 2001; Accepted October 1, 2001 ABSTRACT contribution to the transcription regulation, may vary significantly. Co-operative action of the transcription factors within the CEs Originating from COMPEL, the TRANSCompel data- results in a new highly specific pattern of gene transcription base emphasizes the key role of specific interactions that cannot be provided by the involved factors separately. CEs between transcription factors binding to their target are structural–functional units that provide cross-coupling of sites providing specific features of gene regulation in gene regulatory pathways and, in particular, cross-coupling of a particular cellular content. Composite regulatory signal transduction pathways (3). elements contain two closely situated binding sites There are two main types of CEs: synergistic and antago- for distinct transcription factors and represent nistic. In synergistic CEs, simultaneous interactions of two factors with closely situated target sites results in a non- minimal functional units providing combinatorial additive high level of a transcriptional activation. Within an transcriptional regulation. Both specific factor–DNA antagonistic CE, two factors interfere with each other. and factor–factor interactions contribute to the function The TRANSCompel database originated from the of composite elements (CEs). Information about the COMPEL database (1–8). Several new features have been structure of known CEs and specific gene regulation introduced to improve representation of the composite achieved through such CEs appears to be extremely regulatory elements, and content of the database has been useful for promoter prediction, for gene function significantly increased. prediction and for applied gene engineering as well. Each database entry corresponds to an individual CE CONTENT OF THE DATABASE within a particular gene and contains information about two binding sites, two corresponding transcrip- During the last 2 years, the number of CEs described in the tion factors and experiments confirming cooperative database has increased by ∼30%. Two freely available versions action between transcription factors. The COMPEL of the database have been released, versions 4.4 and 6.0 (Table 1). Distribution of genes among species is as follows: database, equipped with the search and browse 73 human, 40 mouse, 22 rat, 8 chick and 19 others. tools, is available at http://www.gene-regulation.com/ Among recent entries there are CEs containing binding sites pub/databases.html#transcompel. Moreover, we have for the following transcription factors: Smads, 14 entries; developed the program CATCH™ for searching potential CEs in DNA sequences. It is freely available Table1. Content of the TRANSCompel releases 4.4 and 6.0 as CompelPatternSearch at http://compel.bionet.nsc.ru/ FunSite/CompelPatternSearch.html. Number of entries Release 4.4 Release 6.0 INTRODUCTION CEs 202 256 Based on known examples, we define a composite element Genes 131 162 (CE) as a combination of transcription factor binding sites Links to EMBL 171 216 which, as such, and through protein–protein interactions Transcription factors linked to TRANSFAC 171 216 between the transcription factors involved, provides a known regulatory feature (1–3). Thus, interacting factors may differ Interactions 639 948 by the structure of DNA-binding, activation, oligomerization Evidences 602 846 and other domains. Along with structural differences, functional References 207 281 properties of the transcription factors, and hence their specific *To whom correspondence should be addressed at present address: BIOBASE GmbH, Halchtersche Strasse 33, D-38304 Wolfenbuettel, Germany. Tel: +49 5331 858426; Fax: +49 5331 858470; Email: [email protected] Nucleic Acids Research, 2002, Vol. 30, No. 1 333 steroidogenic factor 1, 11 entries; SREBP, 8 entries; AML/PEBP, 4.4 and 6.0 are available at http://www.gene-regulation.com/pub/ 10 entries; PU.1, 19 entries; c-Ets-1,2, 39 entries. databases.html#transcompel; the current professional version We have extended a description of the experimental can be obtained from BIOBASE (http://www.biobase.de; four evidences confirming factor cooperation within CEs. In a separate updates per year). Release COMPEL 3.0 can be found at http:// field we provide information about protein domains involved compel.bionet.nsc.ru/. A detailed description of the fields is in the functional co-operation and/or physical interactions given in the database documentation. Web-based search and between transcription factors. browse options are available. Another new field in the database is devoted to the infor- mation about confirmed or suggested molecular mechanisms CONNECTED PROGRAM of cooperation between transcription factors. The program CATCH™ for searching potential CEs in DNA sequences has been developed. A preliminary version of this CLASSIFICATION OF THE CEs program, CompelPatternSearch, is publicly available at http:// Starting with TRANSCompel 4.4, functional classification of compel.bionet.nsc.ru/FunSite/CompelPatternSearch.html. The the CEs is one of the important features of the database. For current version can be obtained from BIOBASE. A sequence that, we have applied a classification of CEs according to the under study is scanned by this program using all CEs collected specific transcriptional regulation they provide due to co-operative in the TRANSCompel database as individual search patterns. action of transcriptional factors binding to their target sites (3). Several parameters are available, restricting the search: In release 6.0, 200 CEs have been classified into the following maximal mismatches in the cores of site1 and site2 comprising five main groups. the CEs, maximal variation of the distance between two sites, 1. ‘Inducible/inducible’: 81 CEs are formed by binding sites for and composite score cut-off value (6,9). The composite score two inducible factors providing cross-coupling of signal reflects how well the match coincides with the known examples transduction pathways. To this group, we have classified, of the CE in TRANSCompel . This scoring function takes into for instance, 14 CEs within different mammalian genes account the number of mismatches in both sites and the consisting of binding sites for Ets and AP-1 transcription distance between them. All found matches are directly linked factors, providing cross-coupling of Ras/Raf- and PKC- to the TRANSCompel entries containing the corresponding dependent signalling pathways. CEs. 2. ‘Inducible/constitutive’: 39 CEs are composed of binding sites for an inducible and a constitutive ubiquitous factor SUPPLEMENTARY MATERIAL providing some additional features of the inducible regulation. For instance, within Smad/TEF3 and Smad/Sp1 CEs, Supplementary Material is available at NAR Online. Smads are inducible by TGF-β signalling, and TEF3 and Sp1 are constitutive transcription factors. Thus, constitutive factors took an essential part in the regulation by TGF-β. ACKNOWLEDGEMENTS 3. ‘Tissue-restricted/ubiquitous’: 30 CEs are formed by Authors are grateful to N. A. Kolchanov and A. G. Romaschenko binding sites for a tissue-enriched and a constitutive for valuable discussions on the concept of composite regulatory ubiquitous factor providing some additional features of the elements. Part of this work has been funded by Volkswagen- tissue-specific transcriptional regulation. For example, Stiftung (I/75941). steroidogenic cell-restricted transcription factor SF-1 and ubiquitous Sp1 are known to synergistically activate gene expression in steroidogenic cells. REFERENCES 4. ‘Inducible/tissue-restricted’: 27 CEs are constituted by 1. Kel,O.V., Romaschenko,A.G., Kel,A.E., Wingender,E. and Kolchanov,N.A. binding sites for a tissue-enriched and an inducible factor (1995) A compilation of composite regulatory elements affecting gene providing tissue-specific responses to inducing signals. transcription in vertebrates. Nucleic Acids Res., 23, 4097–4103. This group may be illustrated by Pit1/AP-1, Pit1/Ets CEs, 2. Kel,O.V., Romaschenko,A.G., Kel,A.E., Wingender,E. and Kolchanov,N.A. (1997) Composite regulatory elements: classification where Pit1 is a pituitary-restricted transcription factor, and description in the COMPEL database. Mol. Biol., 31, 498–512. whereas AP-1 and Ets are ubiquitous inducible factors. 3. Kel-Margoulis,O.V., Romaschenko,A.G., Kolchanov,N.A., These CEs provide pituitary-restricted induction. Wingender,E. and Kel,A.E. (2000) COMPEL: a database on composite 5. ‘Tissue-restricted/tissue-restricted’: 23 CEs comprise regulatory elements providing combinatorial transcriptional regulation. binding sites for two tissue-enriched factors providing Nucleic Acids Res., 28, 311–315. particular aspects of tissue-specific regulation. For 4. Wingender,E., Kel,A.E., Kel,O.V., Karas,H., Heinemeyer,T., Dietze,P., Knüppel,R., Romaschenko,A.G. and Kolchanov,N.A. (1997) example, Ptx-1 is expressed in all pituitary lineages and TRANSFAC, TRRD and COMPEL: towards a federated database system SF-1 in pituitary gonadotropes only. CEs formed by on transcriptional regulation. Nucleic Acids Res., 25, 265–268. binding sites for these two factors regulate expression of 5. Heinemeyer,T., Wingender,E., Reuter,I., Hermjakob,H., Kel,A.E., genes exclusively in gonadotropes where both factors are Kel,O.V., Ignatieva,E.V., Ananko,E.A., Podkolodnaya,O.A., present. Kolpakov,F.A. et al. (1998) Databases on transcriptional regulation: TRANSFAC, TRRD and COMPEL. Nucleic Acids Res., 26, 362–367. 6. Kel-Margoulis,O.V., Kel,A.E., Frisch,M., Romaschenko,A.G., AVAILABILITY Kolchanov,N.A. and Wingender,E. (1998) COMPEL a database on composite regulatory elements. Proceedings of the First International Being maintained internally as a relational database, TRANS- Conference on Bioinformatics of Genome Regulation and Structure. ICG, Compel is distributed as a single ASCII flat file. Public versions Novosibirsk, Vol. 1, pp. 54–57. 334 Nucleic Acids Research, 2002, Vol. 30, No. 1 7. Heinemeyer,T., Chen,X., Karas,H., Kel,A.E., Kel,O.V., Liebich,I., elements in eukaryotic genes (COMPEL). Proceedings of the Second Meinhardt,T., Reuter,I., Schacherer,F. and Wingender,E. (1999) International Conference on Bioinformatics of Genome Regulation and Expanding of the TRANSFAC database towards an expert system of Structure. ICG, Novosibirsk, Vol. 1, pp. 45–48. regulatory molecular mechanisms. Nucleic Acids Res., 27, 318–322. 9. Kel,A., Kel-Margoulis,O., Babenko,V. and Wingender,E. (1999) 8. Kel-Margoulis,O.V., Romaschenko,A.G., Deineko,I.V., Kolchanov,N.A., Recognition of NFATp/AP-1 composite elements within genes induced Wingender,E. and Kel,A.E. (2000) Database on composite regulatory upon the activation of immune cells. J. Mol. Biol., 288, 353–376. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Nucleic Acids Research Oxford University Press

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

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332–334 Nucleic Acids Research, 2002, Vol. 30, No. 1 © 2002 Oxford University Press TRANSCompel : a database on composite regulatory elements in eukaryotic genes 1,2, 1,2 1 2 Olga V. Kel-Margoulis *, Alexander E. Kel , Ingmar Reuter , Igor V. Deineko and 1,3 Edgar Wingender 1 2 BIOBASE GmbH, Halchtersche Strasse 33, D-38304 Wolfenbüttel, Germany, Institute of Cytology and Genetics SB RAN, 10 Lavrentyev pr., 630090, Novosibirsk, Russia and AG Bioinformatik, Gesellschaft für Biotechnologische Forschung mbH, Mascheroder Weg 1, D-38124 Braunschweig, Germany Received September 24, 2001; Accepted October 1, 2001 ABSTRACT contribution to the transcription regulation, may vary significantly. Co-operative action of the transcription factors within the CEs Originating from COMPEL, the TRANSCompel data- results in a new highly specific pattern of gene transcription base emphasizes the key role of specific interactions that cannot be provided by the involved factors separately. CEs between transcription factors binding to their target are structural–functional units that provide cross-coupling of sites providing specific features of gene regulation in gene regulatory pathways and, in particular, cross-coupling of a particular cellular content. Composite regulatory signal transduction pathways (3). elements contain two closely situated binding sites There are two main types of CEs: synergistic and antago- for distinct transcription factors and represent nistic. In synergistic CEs, simultaneous interactions of two factors with closely situated target sites results in a non- minimal functional units providing combinatorial additive high level of a transcriptional activation. Within an transcriptional regulation. Both specific factor–DNA antagonistic CE, two factors interfere with each other. and factor–factor interactions contribute to the function The TRANSCompel database originated from the of composite elements (CEs). Information about the COMPEL database (1–8). Several new features have been structure of known CEs and specific gene regulation introduced to improve representation of the composite achieved through such CEs appears to be extremely regulatory elements, and content of the database has been useful for promoter prediction, for gene function significantly increased. prediction and for applied gene engineering as well. Each database entry corresponds to an individual CE CONTENT OF THE DATABASE within a particular gene and contains information about two binding sites, two corresponding transcrip- During the last 2 years, the number of CEs described in the tion factors and experiments confirming cooperative database has increased by ∼30%. Two freely available versions action between transcription factors. The COMPEL of the database have been released, versions 4.4 and 6.0 (Table 1). Distribution of genes among species is as follows: database, equipped with the search and browse 73 human, 40 mouse, 22 rat, 8 chick and 19 others. tools, is available at http://www.gene-regulation.com/ Among recent entries there are CEs containing binding sites pub/databases.html#transcompel. Moreover, we have for the following transcription factors: Smads, 14 entries; developed the program CATCH™ for searching potential CEs in DNA sequences. It is freely available Table1. Content of the TRANSCompel releases 4.4 and 6.0 as CompelPatternSearch at http://compel.bionet.nsc.ru/ FunSite/CompelPatternSearch.html. Number of entries Release 4.4 Release 6.0 INTRODUCTION CEs 202 256 Based on known examples, we define a composite element Genes 131 162 (CE) as a combination of transcription factor binding sites Links to EMBL 171 216 which, as such, and through protein–protein interactions Transcription factors linked to TRANSFAC 171 216 between the transcription factors involved, provides a known regulatory feature (1–3). Thus, interacting factors may differ Interactions 639 948 by the structure of DNA-binding, activation, oligomerization Evidences 602 846 and other domains. Along with structural differences, functional References 207 281 properties of the transcription factors, and hence their specific *To whom correspondence should be addressed at present address: BIOBASE GmbH, Halchtersche Strasse 33, D-38304 Wolfenbuettel, Germany. Tel: +49 5331 858426; Fax: +49 5331 858470; Email: [email protected] Nucleic Acids Research, 2002, Vol. 30, No. 1 333 steroidogenic factor 1, 11 entries; SREBP, 8 entries; AML/PEBP, 4.4 and 6.0 are available at http://www.gene-regulation.com/pub/ 10 entries; PU.1, 19 entries; c-Ets-1,2, 39 entries. databases.html#transcompel; the current professional version We have extended a description of the experimental can be obtained from BIOBASE (http://www.biobase.de; four evidences confirming factor cooperation within CEs. In a separate updates per year). Release COMPEL 3.0 can be found at http:// field we provide information about protein domains involved compel.bionet.nsc.ru/. A detailed description of the fields is in the functional co-operation and/or physical interactions given in the database documentation. Web-based search and between transcription factors. browse options are available. Another new field in the database is devoted to the infor- mation about confirmed or suggested molecular mechanisms CONNECTED PROGRAM of cooperation between transcription factors. The program CATCH™ for searching potential CEs in DNA sequences has been developed. A preliminary version of this CLASSIFICATION OF THE CEs program, CompelPatternSearch, is publicly available at http:// Starting with TRANSCompel 4.4, functional classification of compel.bionet.nsc.ru/FunSite/CompelPatternSearch.html. The the CEs is one of the important features of the database. For current version can be obtained from BIOBASE. A sequence that, we have applied a classification of CEs according to the under study is scanned by this program using all CEs collected specific transcriptional regulation they provide due to co-operative in the TRANSCompel database as individual search patterns. action of transcriptional factors binding to their target sites (3). Several parameters are available, restricting the search: In release 6.0, 200 CEs have been classified into the following maximal mismatches in the cores of site1 and site2 comprising five main groups. the CEs, maximal variation of the distance between two sites, 1. ‘Inducible/inducible’: 81 CEs are formed by binding sites for and composite score cut-off value (6,9). The composite score two inducible factors providing cross-coupling of signal reflects how well the match coincides with the known examples transduction pathways. To this group, we have classified, of the CE in TRANSCompel . This scoring function takes into for instance, 14 CEs within different mammalian genes account the number of mismatches in both sites and the consisting of binding sites for Ets and AP-1 transcription distance between them. All found matches are directly linked factors, providing cross-coupling of Ras/Raf- and PKC- to the TRANSCompel entries containing the corresponding dependent signalling pathways. CEs. 2. ‘Inducible/constitutive’: 39 CEs are composed of binding sites for an inducible and a constitutive ubiquitous factor SUPPLEMENTARY MATERIAL providing some additional features of the inducible regulation. For instance, within Smad/TEF3 and Smad/Sp1 CEs, Supplementary Material is available at NAR Online. Smads are inducible by TGF-β signalling, and TEF3 and Sp1 are constitutive transcription factors. Thus, constitutive factors took an essential part in the regulation by TGF-β. ACKNOWLEDGEMENTS 3. ‘Tissue-restricted/ubiquitous’: 30 CEs are formed by Authors are grateful to N. A. Kolchanov and A. G. Romaschenko binding sites for a tissue-enriched and a constitutive for valuable discussions on the concept of composite regulatory ubiquitous factor providing some additional features of the elements. Part of this work has been funded by Volkswagen- tissue-specific transcriptional regulation. For example, Stiftung (I/75941). steroidogenic cell-restricted transcription factor SF-1 and ubiquitous Sp1 are known to synergistically activate gene expression in steroidogenic cells. REFERENCES 4. ‘Inducible/tissue-restricted’: 27 CEs are constituted by 1. Kel,O.V., Romaschenko,A.G., Kel,A.E., Wingender,E. and Kolchanov,N.A. binding sites for a tissue-enriched and an inducible factor (1995) A compilation of composite regulatory elements affecting gene providing tissue-specific responses to inducing signals. transcription in vertebrates. Nucleic Acids Res., 23, 4097–4103. This group may be illustrated by Pit1/AP-1, Pit1/Ets CEs, 2. Kel,O.V., Romaschenko,A.G., Kel,A.E., Wingender,E. and Kolchanov,N.A. (1997) Composite regulatory elements: classification where Pit1 is a pituitary-restricted transcription factor, and description in the COMPEL database. Mol. Biol., 31, 498–512. whereas AP-1 and Ets are ubiquitous inducible factors. 3. Kel-Margoulis,O.V., Romaschenko,A.G., Kolchanov,N.A., These CEs provide pituitary-restricted induction. Wingender,E. and Kel,A.E. (2000) COMPEL: a database on composite 5. ‘Tissue-restricted/tissue-restricted’: 23 CEs comprise regulatory elements providing combinatorial transcriptional regulation. binding sites for two tissue-enriched factors providing Nucleic Acids Res., 28, 311–315. particular aspects of tissue-specific regulation. For 4. Wingender,E., Kel,A.E., Kel,O.V., Karas,H., Heinemeyer,T., Dietze,P., Knüppel,R., Romaschenko,A.G. and Kolchanov,N.A. (1997) example, Ptx-1 is expressed in all pituitary lineages and TRANSFAC, TRRD and COMPEL: towards a federated database system SF-1 in pituitary gonadotropes only. CEs formed by on transcriptional regulation. Nucleic Acids Res., 25, 265–268. binding sites for these two factors regulate expression of 5. Heinemeyer,T., Wingender,E., Reuter,I., Hermjakob,H., Kel,A.E., genes exclusively in gonadotropes where both factors are Kel,O.V., Ignatieva,E.V., Ananko,E.A., Podkolodnaya,O.A., present. Kolpakov,F.A. et al. (1998) Databases on transcriptional regulation: TRANSFAC, TRRD and COMPEL. Nucleic Acids Res., 26, 362–367. 6. Kel-Margoulis,O.V., Kel,A.E., Frisch,M., Romaschenko,A.G., AVAILABILITY Kolchanov,N.A. and Wingender,E. (1998) COMPEL a database on composite regulatory elements. Proceedings of the First International Being maintained internally as a relational database, TRANS- Conference on Bioinformatics of Genome Regulation and Structure. ICG, Compel is distributed as a single ASCII flat file. Public versions Novosibirsk, Vol. 1, pp. 54–57. 334 Nucleic Acids Research, 2002, Vol. 30, No. 1 7. Heinemeyer,T., Chen,X., Karas,H., Kel,A.E., Kel,O.V., Liebich,I., elements in eukaryotic genes (COMPEL). Proceedings of the Second Meinhardt,T., Reuter,I., Schacherer,F. and Wingender,E. (1999) International Conference on Bioinformatics of Genome Regulation and Expanding of the TRANSFAC database towards an expert system of Structure. ICG, Novosibirsk, Vol. 1, pp. 45–48. regulatory molecular mechanisms. Nucleic Acids Res., 27, 318–322. 9. Kel,A., Kel-Margoulis,O., Babenko,V. and Wingender,E. (1999) 8. Kel-Margoulis,O.V., Romaschenko,A.G., Deineko,I.V., Kolchanov,N.A., Recognition of NFATp/AP-1 composite elements within genes induced Wingender,E. and Kel,A.E. (2000) Database on composite regulatory upon the activation of immune cells. J. Mol. Biol., 288, 353–376.

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Nucleic Acids Research – Oxford University Press

Published: Jan 1, 2002

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