Abstract
The cis-element profile (or cis-profile) of a gene refers to the collection of transcription factor binding sites (TFBS) regulating the transcription of the gene. Underlying the various published studies that attempt to discover cis-elements in the vicinity of co-expressed genes via pattern detection algorithms, there is an implicit assumption that a correlation exists between co-expressed genes and their cis-profiles. In this study, we show that the cis-similarity, defined as the proportion of shared TFBS between two cis-element profiles, is higher for functionally linked interacting proteins as well as for members of a signal transduction pathway. A similar analysis of the enzymes catalyzing the conversion of adjacent substrates to products in a collection of metabolic pathways, did not reveal higher cis-similarity. The analysis is based on three distinct sources of publicly available data, namely, 1) the BIND database of interacting proteins, 2) known interactions in NMDAR protein complex, 3) the apoptosis pathway and nine pathways related to metabolism of cofactors and vitamins all from KEGG. Additionally, we analyze the cis-element profiles of all the genes in the glutamate receptor (GR) sub-complex of NMDAR complex to detect a set of cis-elements that occur adjacent to a majority of the genes. We show that most of the corresponding transcription factors are known to be involved in GR regulation by comparing our findings with the published biomedical literature. In addition, we were able to detect transcripts whose gene products associate with GR by searching for transcripts that share the same regulatory signals as those detected for GR. This suggests a novel computational methodology for constructing high-order gene regulatory models and detecting co-regulated gene products.
Similar content being viewed by others
References
G Alexe S Alexe S Foldes PL Hammer (2000) ArticleTitleConsensus algorithms for generation of all maximal bicliques. DIMACS Tech Report 1–20
SF Altschul W Gish W Miller EW Myers DJ Lipman (1990) ArticleTitleBasic local alignment search tool. J Mol Biol 215 403–410 Occurrence Handle10.1006/jmbi.1990.9999 Occurrence Handle1:CAS:528:DyaK3MXitVGmsA%3D%3D Occurrence Handle2231712
GD Bader I Donaldson C Wolting BF Ouellette T Pawson et al. (2001) ArticleTitleBIND–the biomolecular interaction network database. Nucleic Acids Res 29 242–245 Occurrence Handle1:CAS:528:DC%2BD3MXjtlWmtrc%3D Occurrence Handle11125103
PE Bickler PH Donohoe LT Buck (2000) ArticleTitleHypoxia-induced silencing of NMDA receptors in turtle neurons. J Neurosci 20 3522–3528 Occurrence Handle1:CAS:528:DC%2BD3cXjtlKqsro%3D Occurrence Handle10804192
G Chen DV Goeddel (2002) ArticleTitleTNF-R1 signaling: a beautiful pathway. Science 296 1634–1635 Occurrence Handle10.1126/science.1071924 Occurrence Handle1:CAS:528:DC%2BD38XktlChtrg%3D Occurrence Handle12040173
V Chiarugi M Cinelli L Magnelli SP Dello (2002) ArticleTitleApoptosis: molecular regulation of cell death and hematologic malignancies. Mol Biotechnol 20 305–314 Occurrence Handle1:CAS:528:DC%2BD38Xis1Ojtrk%3D Occurrence Handle11936259
RJ Cho M Huang MJ Campbell H Dong L Steinmetz et al. (2001) ArticleTitleTranscriptional regulation and function during the human cell cycle. Nat Genet 27 48–54 Occurrence Handle1:CAS:528:DC%2BD3MXis1yksQ%3D%3D Occurrence Handle11137997
Z Feng RC Chang G Bing P Hudson N Tiao et al. (1999) ArticleTitleLong-term increase of Sp-1 transcription factors in the hippocampus after kainic acid treatment. Brain Res Mol Brain Res 69 144–148 Occurrence Handle10.1016/S0169-328X(99)00099-6 Occurrence Handle1:CAS:528:DyaK1MXjsVShu74%3D Occurrence Handle10350646
S Fessele H Maier C Zischek PJ Nelson T Werner (2002) ArticleTitleRegulatory context is a crucial part of gene function. Trends Genet 18 60–63 Occurrence Handle10.1016/S0168-9525(02)02591-X Occurrence Handle1:CAS:528:DC%2BD38XovFagtQ%3D%3D Occurrence Handle11818130
AC Gavin M Bosche R Krause P Grandi M Marzioch et al. (2002) ArticleTitleFunctional organization of the yeast proteome by systematic analysis of protein complexes. Nature 415 141–147 Occurrence Handle1:CAS:528:DC%2BD38XmsVCgtw%3D%3D Occurrence Handle11805826
H Ge Z Liu GM Church M Vidal (2001) ArticleTitleCorrelation between transcriptome and interactome mapping data from Saccharomyces cerevisiae. Nat Genet 29 482–486 Occurrence Handle1:CAS:528:DC%2BD3MXovFGju7c%3D Occurrence Handle11694880
W Gordon-Krajcer E Salinska JW Lazarewicz (2002) ArticleTitle N-methyl-D-aspartate receptor-mediated processing of beta-amyloid precursor protein in rat hippocampal slices: in vitro–superfusion study. Folia Neuropathol 40 13–17 Occurrence Handle1:CAS:528:DC%2BD3sXht1Sisbc%3D Occurrence Handle12121034
MS Halfon Y Grad GM Church AM Michelson (2002) ArticleTitleComputation-based discovery of related transcriptional regulatory modules and motifs using an experimentally validated combinatorial model. Genome Res 12 1019–1028 Occurrence Handle1:CAS:528:DC%2BD38XlsVWhu7k%3D Occurrence Handle12097338
GZ Hertz GD Stormo (1999) ArticleTitleIdentifying DNA and protein patterns with statistically significant alignments of multiple sequences. Bioinformatics 15 563–577 Occurrence Handle10.1093/bioinformatics/15.7.563 Occurrence Handle1:CAS:528:DyaK1MXntVWitb8%3D Occurrence Handle10487864
H Husi MA Ward JS Choudhary WP Blackstock SG Grant (2000) ArticleTitleProteomic analysis of NMDA receptor-adhesion protein signaling complexes. Nat Neurosci 3 661–669 Occurrence Handle1:CAS:528:DC%2BD3cXkvFaqtrw%3D Occurrence Handle10862698
O Jacobs L Van Bree P Mailleux F Zhang SN Schiffmann et al. (1994) ArticleTitleHomolateral cerebrocortical increase of immediate early gene and neurotransmitter messenger RNAs after minimal cortical lesion: blockade by N-methyl-D-aspartate antagonist. Neuroscience 59 827–836 Occurrence Handle10.1016/0306-4522(94)90287-9 Occurrence Handle1:CAS:528:DyaK2cXis1ajsrk%3D Occurrence Handle7914680
M Kanehisa S Goto S Kawashima A Nakaya (2002) ArticleTitleThe KEGG databases at GenomeNet. Nucleic Acids Res 30 42–46 Occurrence Handle10.1093/nar/30.1.42 Occurrence Handle1:CAS:528:DC%2BD38Xht12ksbc%3D Occurrence Handle11752249
K Kinoshita Y Watanabe M Yamamura Y Matsuoka (1998) ArticleTitleTRH receptor agonists ameliorate 3-acetylpyridine-induced ataxia through NMDA receptors in rats. Eur J Pharmacol 343 129–133 Occurrence Handle10.1016/S0014-2999(97)01539-2 Occurrence Handle1:CAS:528:DyaK1cXhsFejt7Y%3D Occurrence Handle9570459
D Krainc G Bai S Okamoto M Carles JW Kusiak et al. (1998) ArticleTitleSynergistic activation of the N-methyl-D-aspartate receptor subunit 1 promoter by myocyte enhancer factor 2C and Sp1. J Biol Chem 273 26218–26224 Occurrence Handle10.1074/jbc.273.40.26218 Occurrence Handle1:CAS:528:DyaK1cXms1egu7g%3D Occurrence Handle9748305
S Levy S Hannenhalli (2002) ArticleTitleIdentification of transcription factor binding sites in the human genome. Mamm Genome 13 510–514 Occurrence Handle10.1007/s00335-002-2175-6 Occurrence Handle1:CAS:528:DC%2BD38XnsVOgsbk%3D Occurrence Handle12370781
M Markstein P Markstein V Markstein MS Levine (2002) ArticleTitleGenome-wide analysis of clustered dorsal binding sites identifies putative target genes in the Drosophila embryo. Proc Natl Acad Sci USA 99 763–768 Occurrence Handle10.1073/pnas.012591199 Occurrence Handle1:CAS:528:DC%2BD38Xht1Wisr0%3D Occurrence Handle11752406
SS Mostafa ET Papoutsakis WM Miller (2001) ArticleTitleOxygen tension modulates the expression of cytokine receptors, transcription factors, and lineage-specific markers in cultured human megakaryocytes. Exp Hematol 29 873–883 Occurrence Handle10.1016/S0301-472X(01)00658-0 Occurrence Handle1:CAS:528:DC%2BD3MXks1OksLk%3D Occurrence Handle11438210
I Pieri M Klein C Bayertz J Gerspach A van der Ploeg et al. (1999) ArticleTitleRegulation of the murine NMDA-receptor-subunit NR2C promoter by Sp1 and fushi tarazu factor1 (FTZ-F1) homologues. Eur J Neurosci 11 2083–2092 Occurrence Handle10.1046/j.1460-9568.1999.00629.x Occurrence Handle1:STN:280:DyaK1M3mvV2gtA%3D%3D Occurrence Handle10336677
J Platenik N Kuramoto Y Yoneda (2000) ArticleTitleMolecular mechanisms associated with long-term consolidation of the NMDA signals. Life Sci 67 335–364 Occurrence Handle10.1016/S0024-3205(00)00632-9 Occurrence Handle1:CAS:528:DC%2BD3cXktl2ntrc%3D Occurrence Handle11003045
M Ptashne A Gann (1998) ArticleTitleImposing specificity by localization: mechanism and evolvability. Curr Biol 8 R812–R822 Occurrence Handle1:CAS:528:DyaK1cXnt1Grsro%3D Occurrence Handle9818164
C Sevoz-Couche B Maisonneuve M Hamon R Laguzzi (2002) ArticleTitleGlutamate and NO mediation of the pressor response to 5-HT3 receptor stimulation in the nucleus tractus solitarii. Neuroreport 13 837–841 Occurrence Handle1:CAS:528:DC%2BD38XnsFKkt74%3D Occurrence Handle11997697
SD Sorensen TA Macek Z Cai JA Saugstad PJ Conn (2002) ArticleTitleDissociation of protein kinase-mediated regulation of metabotropic glutamate receptor 7 (mGluR7) interactions with calmodulin and regulation of mGluR7 function. Mol Pharmacol 61 1303–1312 Occurrence Handle10.1124/mol.61.6.1303 Occurrence Handle1:CAS:528:DC%2BD38XksVWrt70%3D Occurrence Handle12021391
R Sosa B Hoffpauir ML Rankin RC Bruch L Gleason (2002) ArticleTitleMetabotropic glutamate receptor 5 and calcium signaling in retinal amacrine cells. J Neurochem 81 973–983 Occurrence Handle10.1046/j.1471-4159.2002.00883.x Occurrence Handle1:CAS:528:DC%2BD38XksV2hsrs%3D Occurrence Handle12065609
LM Staudt PO Brown (2000) ArticleTitleGenomic views of the immune system. Annu Rev Immunol 18 829–859
P Washbourne JE Bennett AK McAllister (2002) ArticleTitleRapid recruitment of NMDA receptor transport packets to nascent synapses. Nat Neurosci 5 751–759 Occurrence Handle1:CAS:528:DC%2BD38XlsFaqu7s%3D Occurrence Handle12089529
E Wingender X Chen E Fricke R Geffers R Hehl et al. (2001) ArticleTitleThe TRANSFAC system on gene expression regulation. Nucleic Acids Res 29 281–283 Occurrence Handle10.1093/nar/29.1.281 Occurrence Handle1:CAS:528:DC%2BD3MXjtlWmtL4%3D Occurrence Handle11125113
WM Yee DM Frim O Isacson (1993) ArticleTitleRelationships between stress protein induction and NMDA-mediated neuronal death in the entorhinal cortex. Exp Brain Res 94 193–202 Occurrence Handle1:CAS:528:DyaK3sXlsFOntbY%3D Occurrence Handle8395405
Acknowledgements
The authors thank Joseph Nadeau, Mike Flanigan, and the anonymous reviewers for providing helpful comments toward improving the manuscript.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Hannenhalli, S., Levy, S. Transcriptional regulation of protein complexes and biological pathways . Mamm Genome 14, 611–619 (2003). https://doi.org/10.1007/s00335-002-2260-x
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/s00335-002-2260-x