Genes and Immunity (2007) 8, 360–365 & 2007 Nature Publishing Group All rights reserved 1466-4879/07 $30.00 www.nature.com/gene SHORT COMMUNICATION LymphTF-DB: a database of transcription factors involved in lymphocyte development PJ Childress, RL Fletcher and NB Perumal School of Informatics, Indiana University-Purdue University Indianapolis, Indianapolis, IN, USA B and T cells develop following a similar early stepwise progression to later stages where multiple developmental options are available. These developmental regimes necessitate differential gene expression regulated by a large number of transcription factors (TFs). The resultant burgeoning amount of information has opened a knowledge gap between TF activities during lymphocyte development and a researcher’s experiments. We have created the LymphTF database (DB) to fill this gap. This DB holds interactions between individual TFs and their specific targets at a given developmental time. By storing such interactions as a function of developmental progression, we hope to advance the elucidation of regulatory networks that guide lymphocyte development. Besides queries for TF-target gene interactions in developmental stages, the DB provides a graphical representation of downloadable target gene regulatory sequences with locations of the transcriptional start sites and TF-binding sites. The LymphTF-DB can be accessed freely on the web at http://www.iupui.edu/~tfinterx/. Genes and Immunity (2007) 8, 360–365; doi:10.1038/sj.gene.6364386; published online 15 March 2007 Keywords: transcription factors; targets; lymphocyte development; database Introduction the discovery of new targets and transcription factors important in the process of lymphocyte development.7,8 Research in mammalian lymphocyte development has Interpretation of results from these high-throughput benefited from improvements in molecular sorting and experiments is, however, not always straight forward. identification techniques as well as from the use of the Further studies are needed to describe properly a factor’s mouse as a robust model system. The result is a field of place in the transcriptional regulation hierarchy. Com- study that has produced a very large amount of data. plicating matters further is the context-specific action of Additionally, lymphocyte development from progenitor some transcription factors. For example, the zinc-finger stem cells provides a model for studying more general protein Ikaros is involved in chromatin remodeling development paradigms and has most recently been complexes and has been shown to have simultaneous shown to have clinical significance in understanding the activation and repressive function within the same cell process of terminal differentiation. The development of type and stage of development.9,10 Recently many good the major lymphocytic cell types, B and T cells, is at the reviews have been written that attempt to highlight the center of gene expression studies. In this system, many key players involved in the development of these two well-defined milestones in the development process, and cell types. However, given the breadth of information molecular pathways determining cell fate have been available these reviews typically focus on a specific part described. These cells undergo similar transitions be- of the process such as early B-cell development, a tween stages dependent upon both anatomical location particular transcription factor such as NF-kB, or include and exogenous stimulation from immune stimuli.1,2 only a portion of the TFs and targets involved.5,6,11,12 The complex lymphocyte developmental regime is The explosion of data has led to the issue of dependent upon changing patterns of gene expression information management becoming a critical concern in that are accomplished, in part, by the action of specific this field of study. The scientific community has begun transcription factors (TF) on their targets. This action is a to address this issue through a variety of ways. The dynamic and generally a conserved chorus of events.3,4 TRANSFAC (http://www.gene-regulation.com/pub/ Since the early 1990s the work in this field has produced databases.html), JASPAR (http://jaspar.cgb.ki.se/cgi-bin/ a steady stream of well-defined TF-target gene inter- jaspar_db.pl) and TESS (http://www.cbil.upenn.edu/ actions.5,6 More recently, DNA microarrays have aided tess) databases are intended for use by wide audiences for general transcriptional regulation studies. These databases mix computationally predicted transcription Correspondence: Dr NB Perumal, School of Informatics, Indiana factor-binding sites (TFBS) with biologically validated University-Purdue University Indianapolis, 719 Indiana Avenue data on TF-target interactions. Research in lymphocyte Suite 311, Indianapolis, IN 46202, USA. E-mail: [email protected] development in the post-genomics era has benefited Received 21 September 2006; revised and accepted 1 February 2007; from specialized databases. This is due, in part, to the published online 15 March 2007 numbers of transcription factors and targets involved, Database of TF activity in lymphocyte development PJ Childress et al 361 Table 1 Search results for TF-target gene interactions of Bcl6 Activity Target gene B-cell stage T-cell stage Reference(s) Evidence Results for Bcl6 (rollover names for aliases) Represses Bcl6 Mature B Tunyaplin et al.17 tt em nb ci Represses Ccl3 Immature B Shaffer et al.7 ma em nb tt Represses Ccnd2 Immature B Shaffer et al.7 ma em nb tt Represses Cd44 Immature B Shaffer et al.7 ma nb tt Represses Cd69 Immature B Shaffer et al.7 ma em nb tt Represses Cd80 Mature B Niu et al.21 rp tt ci fc Represses Cdkn1b Immature B Shaffer et al.7 ma nb tt Represses Fcer1g Th2 Dent et al.22 em tt Represses Gata3 Th2 Kusam et al.23 ko rp wb tt ia Represses Igh-7 Lymphoblast Harris et al.24 tt em ph Represses Il13 Th2 Dent et al.22 rpa ia Represses Il4 Th2 Dent et al.22 rpa ia Represses Il5 SP (+4) Arima et al.25 em ci tt mu Represses Il5 Th1 Arima et al.25 em ci tt mu Represses Il5 Th2 Arima et al.25 em ci tt mu Represses Il6 Th2 Dent et al.22 rpa ia Represses Prdm1 Immature B Tunyaplin et al.17 tt fp ci ko rp Represses Prdm1 Mature B Tunyaplin et al.17 tt fp ci ko rp Represses Trp53 Mature B Phan et al.26 tt ci kd ts The raw data for information in the DB comes from peer-reviewed, published scientific articles that are available from the National Library of Medicine’s PubMed DB. In an attempt to obtain current and relevant data, articles published before 1985 were excluded. Keyword searches (e.g., ‘Transcription factors and T [or B]-cell development’) were performed using the NCBI’s Entrez search engine. Relevant articles were culled from thousands obtained by initially screening titles and abstracts for their potential to be included in our database. In the second and subsequent rounds of annotation, selected articles were carefully read for collection of data regarding TFs, target genes, developmental stages of expression, and experimental evidence supporting TF–target gene interactions. We have included only murine data in the LymphTF-DB. Users can search for any transcription factor or target gene by its official name or alias from the home page of the website. It is not necessary to input literal values; the search function also accepts wild card values. The combination of a MySQL database searched via a web page front end utilizing the PHP scripting language has been used to present the information in a freely available format. and the transient nature of these interactions. Apparently logists studying lymphocyte development and develop- contradictory phenomena, such as Ikaros mentioned mental biologists exploring transcriptional regulatory above, may indicate complex modes of action for the TFs networks (TRN).15–18 involved. Researchers also need to be aware of the type of evidence associated with each interaction to fully understand the regulatory mechanisms involved. The Results and discussion HemoPDB (http://bioinformatics.med.ohio-state.edu/ HemoPDB/) contains information related to transcrip- Review of relevant literature has resulted in the collec- tional control of hematopoiesis including promoter tion and cataloging of 111 unique transcription factors sequences and cis-regulatory elements for transcription involved or implicated in B- or T-cell development at the factors.13 The Immunogenetics group at Universite´ time of publication. This number represents 55 factors for Montpellier II, Montpellier, France has assembled the which interactions with a specific target gene have been IMGT/GENE-DB (http://imgt.cines.fr/cgi-bin/GEN- shown, and an additional 56 factors that have been Elect.jv?livret ¼ 0) specific for human and mouse im- shown to be present or transcriptionally active during B- munoglobulin and T-cell receptor genes.14 These are just and T-cell development. These TFs are presented in the two examples of the community addressing the informa- DB with commonly used aliases and links to the factor’s tion management issues for specific collections of data in entry in the Gene DB at NCBI.19 The LymphTF-DB the field of lymphopoiesis. From these domain-specific contains a total of 110 target genes. As with the TFs, each databases researchers hope to piece together a complete target is linked to a Gene DB entry and common aliases picture of gene expression and molecular function. are stored in the DB. The total number of interactions in Here, we present an approach to capture published the DB is 388. Of these 388 interactions, 205 interactions molecular interactions in B-and T-cell development. The constitute unique TF-target pairs with experimental LymphTF-DB (http://www.iupui.edu/~tfinterx) is a evidence of interactions in various lymphoid develop- manually curated DB of transcription factors and their mental stages. Further, we have identified 51 TF–TF activity on specific target genes at various developmental interactions wherein one TF activates or represses stages in the mouse.