Integrating bioinformatic resources to predict transcription factors interacting with cis-sequences conserved in co-regulated genes

BMC Genomics

Reinhard Hehl¹  Bruno Contreras-Moreira⁵  Bernd Weisshaar⁴  Loïc Lepiniec²  Cecile Brousse²  Fabien Salsac²  Damaris Grain²  Wenjia Xu²  Gunnar Huep⁴  Lorenz Bülow¹  Alvaro Sebastian⁶  Zsolt Kelemen³  Christian Dubos⁷ 

[1] Institut für Genetik, Technische Universität Braunschweig, Spielmannstr. 7, 38106 Braunschweig, Germany;INRA, Institut Jean-Pierre Bourgin, Saclay Plant Sciences, UMR1318, RD10, F-78026, Versailles, France;AgroParisTech, Institut Jean-Pierre Bourgin, Saclay Plant Sciences, UMR1318, RD10, F-78026, Versailles, France;Department of Biology, Bielefeld University, Universitaetsstrasse 25, 33615 Bielefeld, Germany;Fundación ARAID, calle María de Luna 11, 50018 Zaragoza, Spain;Estación Experimental de Aula Dei/CSIC, Av. Montañana 1.005, 50059 Zaragoza, Spain;Current address: Biochimie et Physiologie Moleculaire des Plantes, UMR 5004, INRA/CNRS/SupAgro-M/UM2, 34060 Montpellier Cedex 1, France

关键词: cis-element;    Transcription factor;    Microarray;    Yeast one-hybrid;    Physcomitrella patens;    Arabidopsis thaliana;    Databases;   

Others  :  1217397
DOI  :  10.1186/1471-2164-15-317

 received in 2013-11-08, accepted in 2014-04-16,  发布年份 2014

【 摘 要 】

Background

Using motif detection programs it is fairly straightforward to identify conserved cis-sequences in promoters of co-regulated genes. In contrast, the identification of the transcription factors (TFs) interacting with these cis-sequences is much more elaborate. To facilitate this, we explore the possibility of using several bioinformatic and experimental approaches for TF identification. This starts with the selection of co-regulated gene sets and leads first to the prediction and then to the experimental validation of TFs interacting with cis-sequences conserved in the promoters of these co-regulated genes.

Results

Using the PathoPlant database, 32 up-regulated gene groups were identified with microarray data for drought-responsive gene expression from Arabidopsis thaliana. Application of the binding site estimation suite of tools (BEST) discovered 179 conserved sequence motifs within the corresponding promoters. Using the STAMP web-server, 49 sequence motifs were classified into 7 motif families for which similarities with known cis-regulatory sequences were identified. All motifs were subjected to a footprintDB analysis to predict interacting DNA binding domains from plant TF families. Predictions were confirmed by using a yeast-one-hybrid approach to select interacting TFs belonging to the predicted TF families. TF-DNA interactions were further experimentally validated in yeast and with a Physcomitrella patens transient expression system, leading to the discovery of several novel TF-DNA interactions.

Conclusions

The present work demonstrates the successful integration of several bioinformatic resources with experimental approaches to predict and validate TFs interacting with conserved sequence motifs in co-regulated genes.

【 授权许可】

   
2014 Dubos et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

Figure 4.

Figure 5.

【 参考文献 】

• [1]Harb A, Krishnan A, Ambavaram MM, Pereira A: Molecular and physiological analysis of drought stress in Arabidopsis reveals early responses leading to acclimation in plant growth. Plant Physiol 2010, 154:1254-1271.
• [2]Zou C, Sun K, Mackaluso JD, Seddon AE, Jin R, Thomashow MF, Shiu SH: Cis-regulatory code of stress-responsive transcription in Arabidopsis thaliana. Proc Natl Acad Sci U S A 2011, 108:14992-14997.
• [3]Koschmann J, Machens F, Becker M, Niemeyer J, Schulze J, Bülow L, Stahl DJ, Hehl R: Integration of bioinformatics and synthetic promoters leads to the discovery of novel elicitor-responsive cis-regulatory sequences in Arabidopsis. Plant Physiol 2012, 160:178-191.
• [4]Hehl R, Wingender E: Database-assisted promoter analysis. Trends Plant Sci 2001, 6:251-255.
• [5]Hehl R, Steffens NO, Wingender E: Isolation and analysis of gene regulatory sequences. In Handbook of Plant Biotechnology. Edited by Christou P, Klee H. Weinheim Germany: John Wiley and Sons Ltd; 2004:81-102.
• [6]Hehl R, Bülow L: Internet resources for gene expression analysis in Arabidopsis thaliana. Curr Genomics 2008, 9:375-380.
• [7]Brady SM, Provart NJ: Web-queryable large-scale data sets for hypothesis generation in plant biology. Plant Cell 2009, 21:1034-1051.
• [8]Priest HD, Filichkin SA, Mockler TC: Cis-Regulatory elements in plant cell signaling. Curr Opin Plant Biol 2009, 12:643-649.
• [9]Usadel B, Obayashi T, Mutwil M, Giorgi FM, Bassel GW, Tanimoto M, Chow A, Steinhauser D, Persson S, Provart NJ: Co-expression tools for plant biology: opportunities for hypothesis generation and caveats. Plant Cell Environ 2009, 32:1633-1651.
• [10]Galuschka C, Schindler M, Bülow L, Hehl R: AthaMap web-tools for the analysis and identification of co-regulated genes. Nucleic Acids Res 2007, 35:D857-D862.
• [11]Chang WC, Lee TY, Huang HD, Huang HY, Pan RL: PlantPAN: Plant promoter analysis navigator, for identifying combinatorial cis-regulatory elements with distance constraint in plant gene groups. BMC Genomics 2008, 9:561. BioMed Central Full Text
• [12]Bülow L, Engelmann S, Schindler M, Hehl R: AthaMap, integrating transcriptional and post-transcriptional data. Nucleic Acids Res 2009, 37:D983-D986.
• [13]Bailey TL, Elkan C: The value of prior knowledge in discovering motifs with MEME. Proc Int Conf Intell Syst Mol Biol 1995, 3:21-29.
• [14]Roth FP, Hughes JD, Estep PW, Church GM: Finding DNA regulatory motifs within unaligned noncoding sequences clustered by whole-genome mRNA quantitation. Nat Biotechnol 1998, 16:939-945.
• [15]Hertz GZ, Stormo GD: Identifying DNA and protein patterns with statistically significant alignments of multiple sequences. Bioinformatics 1999, 15:563-577.
• [16]GuhaThakurta D, Stormo GD: Identifying target sites for cooperatively binding factors. Bioinformatics 2001, 17:608-621.
• [17]Liu X, Brutlag DL, Liu JS: BioProspector: discovering conserved DNA motifs in upstream regulatory regions of co-expressed genes. Pac Symp Biocomput 2001, 127-138.
• [18]Eskin E, Pevzner PA: Finding composite regulatory patterns in DNA sequences. Bioinformatics 2002, 18(Suppl 1):S354-S363.
• [19]Che D, Jensen S, Cai L, Liu JS: BEST: binding-site estimation suite of tools. Bioinformatics 2005, 21:2909-2911.
• [20]Bülow L, Schindler M, Choi C, Hehl R: PathoPlant: A database on plant-pathogen interactions. In Silico Biol 2004, 4:529-536.
• [21]Bülow L, Schindler M, Hehl R: PathoPlant: a platform for microarray expression data to analyze co-regulated genes involved in plant defense responses. Nucleic Acids Res 2007, 35:D841-D845.
• [22]Mahony S, Benos PV: STAMP: a web tool for exploring DNA-binding motif similarities. Nucleic Acids Res 2007, 35:W253-W258.
• [23]Higo K, Ugawa Y, Iwamoto M, Korenaga T: Plant cis-acting regulatory DNA elements (PLACE) database: 1999. Nucleic Acids Res 1999, 27:297-300.
• [24]Davuluri RV, Sun H, Palaniswamy SK, Matthews N, Molina C, Kurtz M, Grotewold E: AGRIS: Arabidopsis Gene Regulatory Information Server, an information resource of Arabidopsis cis-regulatory elements and transcription factors. BMC Bioinformatics 2003, 4:25. BioMed Central Full Text
• [25]Steffens NO, Galuschka C, Schindler M, Bülow L, Hehl R: AthaMap: an online resource for in silico transcription factor binding sites in the Arabidopsis thaliana genome. Nucleic Acids Res 2004, 32:D368-D372.
• [26]Bülow L, Steffens NO, Galuschka C, Schindler M, Hehl R: AthaMap: from in silico data to real transcription factor binding sites. In Silico Biol 2006, 6:243-252.
• [27]Palaniswamy SK, James S, Sun H, Lamb RS, Davuluri RV, Grotewold E: AGRIS and AtRegNet. a platform to link cis-regulatory elements and transcription factors into regulatory networks. Plant Physiol 2006, 140:818-829.
• [28]Yilmaz A, Mejia-Guerra MK, Kurz K, Liang X, Welch L, Grotewold E: AGRIS: the Arabidopsis Gene Regulatory Information Server, an update. Nucleic Acids Res 2011, 39:D1118-D1122.
• [29]Contreras-Moreira B: 3D-footprint: a database for the structural analysis of protein-DNA complexes. Nucleic Acids Res 2010, 38:D91-D97.
• [30]Sebastian A, Contreras-Moreira B: footprintDB: a database of transcription factors with annotated cis elements and binding interfaces. Bioinformatics 2014, 30:258-265.
• [31]Bolívar JC, Machens F, Brill Y, Romanov A, Bülow L, Hehl R: 'In silico expression analysis’, a novel PathoPlant web-tool to identify abiotic and biotic stress conditions associated with specific cis-regulatory sequences. Database (Oxford) 2014, 2014:bau030.
• [32]Tamura K, Dudley J, Nei M, Kumar S: MEGA4: Molecular Evolutionary Genetics Analysis (MEGA) software version 4.0. Mol Biol Evol 2007, 24:1596-1599.
• [33]Giuliano G, Pichersky E, Malik VS, Timko MP, Scolnik PA, Cashmore AR: An evolutionarily conserved protein binding sequence upstream of a plant light-regulated gene. Proc Natl Acad Sci U S A 1988, 85:7089-7093.
• [34]Guiltinan MJ, Marcotte WR Jr, Quatrano RS: A plant leucine zipper protein that recognizes an abscisic acid response element. Science 1990, 250:267-271.
• [35]Iwasaki T, Yamaguchi-Shinozaki K, Shinozaki K: Identification of a cis-regulatory region of a gene in Arabidopsis thaliana whose induction by dehydration is mediated by abscisic acid and requires protein synthesis. Mol Gen Genet 1995, 247:391-398.
• [36]Ono A, Izawa T, Chua NH, Shimamoto K: The rab16B promoter of rice contains two distinct abscisic acid-responsive elements. Plant Physiol 1996, 112:483-491.
• [37]Busk PK, Pages M: Protein binding to the abscisic acid-responsive element is independent of VIVIPAROUS1 in vivo. Plant Cell 1997, 9:2261-2270.
• [38]Jakoby M, Weisshaar B, Dröge-Laser W, Vicente-Carbajosa J, Tiedemann J, Kroj T, Parcy F: bZIP transcription factors in Arabidopsis. Trends Plant Sci 2002, 7:106-111.
• [39]Correa LG, Riano-Pachon DM, Schrago CG, dos Santos RV, Mueller-Roeber B, Vincentz M: The role of bZIP transcription factors in green plant evolution: adaptive features emerging from four founder genes. PLoS One 2008, 3:e2944.
• [40]Matys V, Fricke E, Geffers R, Gossling E, Haubrock M, Hehl R, Hornischer K, Karas D, Kel AE, Kel-Margoulis OV, Kloos DU, Land S, Lewicki-Potapov B, Michael H, Münch R, Reuter I, Rotert S, Saxel H, Scheer M, Thiele S, Wingender E: TRANSFAC: transcriptional regulation, from patterns to profiles. Nucleic Acids Res 2003, 31:374-378.
• [41]Sandelin A, Alkema W, Engstrom P, Wasserman WW, Lenhard B: JASPAR: an open-access database for eukaryotic transcription factor binding profiles. Nucleic Acids Res 2004, 32:D91-D94.
• [42]Bülow L, Bolívar JC, Ruhe J, Brill Y, Hehl R: MicroRNA Targets’A new AthaMap web-tool for genome-wide identification of miRNA targets in Arabidopsis thaliana. Bio Data Min 2012, 5:7.
• [43]Xu W, Grain D, Le Gourrierec J, Harscoet E, Berger A, Jauvion V, Scagnelli A, Berger N, Bidzinski P, Kelemen Z, Salsac F, Baudry A, Routaboul JM, Lepiniec L, Dubos C: Regulation of flavonoid biosynthesis involves an unexpected complex transcriptional regulation of TT8 expression, in Arabidopsis. New Phytol 2013, 198:59-70.
• [44]Zhang Y, Mayba O, Pfeiffer A, Shi H, Tepperman JM, Speed TP, Quail PH: A Quartet of PIF bHLH Factors provides a transcriptionally centered signaling hub that regulates seedling morphogenesis through differential expression-patterning of shared target genes in Arabidopsis. PLoS Genet 2013, 9:e1003244.
• [45]Tran LS, Nakashima K, Sakuma Y, Simpson SD, Fujita Y, Maruyama K, Fujita M, Seki M, Shinozaki K, Yamaguchi-Shinozaki K: Isolation and functional analysis of Arabidopsis stress-inducible NAC transcription factors that bind to a drought-responsive cis-element in the early responsive to dehydration stress 1 promoter. Plant Cell 2004, 16:2481-2498.
• [46]Olsen AN, Ernst HA, Lo Leggio L, Skriver K: DNA-binding specificity and molecular functions of NAC transcription factors. Plant Sci 2005, 169:785-797.
• [47]Ogo Y, Kobayashi T, Nakanishi Itai R, Nakanishi H, Kakei Y, Takahashi M, Toki S, Mori S, Nishizawa NK: A novel NAC transcription factor, IDEF2, that recognizes the iron deficiency-responsive element 2 regulates the genes involved in iron homeostasis in plants. J Biol Chem 2008, 283:13407-13417.
• [48]Patzlaff A, Newman LJ, Dubos C, Whetten RW, Smith C, McInnis S, Bevan MW, Sederoff RR, Campbell MM: Characterisation of Pt MYB1, an R2R3-MYB from pine xylem. Plant Mol Biol 2003, 53:597-608.
• [49]Prouse MB, Campbell MM: The interaction between MYB proteins and their target DNA binding sites. Biochim Biophys Acta 1819, 2012:67-77.
• [50]Romano JM, Dubos C, Prouse MB, Wilkins O, Hong H, Poole M, Kang KY, Li E, Douglas CJ, Western TL, Mansfield SD, Campbell MM: AtMYB61, an R2R3-MYB transcription factor, functions as a pleiotropic regulator via a small gene network. New Phytol 2012, 195:774-786.
• [51]Dubos C, Stracke R, Grotewold E, Weisshaar B, Martin C, Lepiniec L: MYB transcription factors in Arabidopsis. Trends Plant Sci 2010, 15:573-581.
• [52]Albani D, Hammond-Kosack MC, Smith C, Conlan S, Colot V, Holdsworth M, Bevan MW: The wheat transcriptional activator SPA: a seed-specific bZIP protein that recognizes the GCN4-like motif in the bifactorial endosperm box of prolamin genes. Plant Cell 1997, 9:171-184.
• [53]Duval M, Hsieh TF, Kim SY, Thomas TL: Molecular characterization of AtNAM: a member of the Arabidopsis NAC domain superfamily. Plant Mol Biol 2002, 50:237-248.
• [54]Zhang K, Gan SS: An abscisic acid-AtNAP transcription factor-SAG113 protein phosphatase 2C regulatory chain for controlling dehydration in senescing Arabidopsis leaves. Plant Physiol 2012, 158:961-969.
• [55]Wang X, Culver JN: DNA binding specificity of ATAF2, a NAC domain transcription factor targeted for degradation by Tobacco mosaic virus. BMC Plant Biol 2012, 12:157. BioMed Central Full Text
• [56]Nakashima K, Takasaki H, Mizoi J, Shinozaki K, Yamaguchi-Shinozaki K: NAC transcription factors in plant abiotic stress responses. Biochim Biophys Acta 2012, 1819:97-103.
• [57]Singh KB: Transcriptional regulation in plants: the importance of combinatorial control. Plant Physiol 1998, 118:1111-1120.
• [58]Wan J, Zhang XC, Neece D, Ramonell KM, Clough S, Kim SY, Stacey MG, Stacey G: A LysM receptor-like kinase plays a critical role in chitin signaling and fungal resistance in Arabidopsis. Plant Cell 2008, 20:471-481.
• [59]Romero I, Fuertes A, Benito MJ, Malpica JM, Leyva A, Paz-Ares J: More than 80R2R3-MYB regulatory genes in the genome of Arabidopsis thaliana. Plant J 1998, 14:273-284.
• [60]Prouse MB, Campbell MM: Interactions between the R2R3-MYB Transcription Factor, AtMYB61, and Target DNA Binding Sites. PLoS One 2013, 8:e65132.
• [61]Kilian J, Whitehead D, Horak J, Wanke D, Weinl S, Batistic O, D’Angelo C, Bornberg-Bauer E, Kudla J, Harter K: The AtGenExpress global stress expression data set: protocols, evaluation and model data analysis of UV-B light, drought and cold stress responses. Plant J 2007, 50:347-363.
• [62]Craigon DJ, James N, Okyere J, Higgins J, Jotham J, May S: NASCArrays: a repository for microarray data generated by NASC's transcriptomics service. Nucleic Acids Res 2004, 32:D575-D577.
• [63]Hubbell E, Liu WM, Mei R: Robust estimators for expression analysis. Bioinformatics 2002, 18:1585-1592.
• [64]Lamesch P, Berardini TZ, Li D, Swarbreck D, Wilks C, Sasidharan R, Muller R, Dreher K, Alexander DL, Garcia-Hernandez M, Karthikeyan AS, Lee CH, Nelson WD, Ploetz L, Singh S, Wensel A, Huala E: The Arabidopsis Information Resource (TAIR): improved gene annotation and new tools. Nucleic Acids Res 2012, 40:D1202-D1210.
• [65]Stormo GD: DNA binding sites: representation and discovery. Bioinformatics 2000, 16:16-23.
• [66]Robasky K, Bulyk ML: UniPROBE, update 2011: expanded content and search tools in the online database of protein-binding microarray data on protein-DNA interactions. Nucleic Acids Res 2011, 39:D124-D128.
• [67]Sierro N, Makita Y, de Hoon M, Nakai K: DBTBS: a database of transcriptional regulation in Bacillus subtilis containing upstream intergenic conservation information. Nucleic Acids Res 2008, 36:D93-D96.
• [68]Salgado H, Peralta-Gil M, Gama-Castro S, Santos-Zavaleta A, Muniz-Rascado L, Garcia-Sotelo JS, Weiss V, Solano-Lira H, Martinez-Flores I, Medina-Rivera A, Salgado-Osorio G, Alquicira-Hernandez S, Alquicira-Hernandez K, Lopez-Fuentes A, Porron-Sotelo L, Huerta AM, Bonavides-Martinez C, Balderas-Martinez YI, Pannier L, Olvera M, Labastida A, Jimenez-Jacinto V, Vega-Alvarado L, Del Moral-Chavez V, Hernandez-Alvarez A, Morett E, Collado-Vides J: RegulonDB v8.0: omics data sets, evolutionary conservation, regulatory phrases, cross-validated gold standards and more. Nucleic Acids Res 2013, 41:D203-D213.
• [69]Down TA, Bergman CM, Su J, Hubbard TJ: Large-scale discovery of promoter motifs in Drosophila melanogaster. PLoS Comput Biol 2007, 3:e7.
• [70]Jolma A, Yan J, Whitington T, Toivonen J, Nitta KR, Rastas P, Morgunova E, Enge M, Taipale M, Wei G, Palin K, Vaquerizas JM, Vincentelli R, Luscombe NM, Hughes TR, Lemaire P, Ukkonen E, Kivioja T, Taipale J: DNA-binding specificities of human transcription factors. Cell 2013, 152:327-339.
• [71]Paz-Ares J, Regia Consortium: REGIA, an EU project on functional genomics of transcription factors from Arabidopsis Thaliana. Comp Funct Genomics 2002, 3:102-108.
• [72]Castrillo G, Turck F, Leveugle M, Lecharny A, Carbonero P, Coupland G, Paz-Ares J, Onate-Sanchez L: Speeding cis-trans regulation discovery by phylogenomic analyses coupled with screenings of an arrayed library of Arabidopsis transcription factors. PLoS One 2011, 6:e21524.
• [73]Sebastian A, Contreras-Moreira B: The twilight zone of cis element alignments. Nucleic Acids Res 2013, 41:1438-1449.
• [74]Thevenin J, Dubos C, Xu W, Le Gourrierec J, Kelemen Z, Charlot F, Nogue F, Lepiniec L, Dubreucq B: A new system for fast and quantitative analysis of heterologous gene expression in plants. New Phytol 2012, 193:504-512.