Nature Biotechnology
16, 939 - 945 (1998)
doi:10.1038/nbt1098-939
Finding DNA regulatory motifs within unaligned noncoding sequences clustered by whole-genome mRNA quantitationFrederick P. Roth1, 2, 3, †, Jason D. Hughes1, 2, †, Preston W. Estep2
& George M. Church1, 2, *
1Harvard University Graduate Biophysics Program, Boston, MA 02115.
2Harvard Medical School Department of Genetics, Boston, MA 02115.
3Current address: Millennium Information, Cambridge, MA 02139.
*Corresponding author (e-mail: church@salt2.med.harvard.edu)
†These authors contributed equally to this work Whole-genome mRNA quantitation can be used to identify the genes that are most responsive to environmental or genotypic change. By searching for mutually similar DNA elements among the upstream non-coding DNA sequences of these genes, we can identify candidate regulatory motifs and corresponding candidate sets of coregulated genes. We have tested this strategy by applying it to three extensively studied regulatory systems in the yeast Saccharomyces cerevisiae: galactose response, heat shock, and mating type. Galactose-response data yielded the known binding site of Gal4, and six of nine genes known to be induced by galactose. Heat shock data yielded the cell-cycle activation motif, which is known to mediate cell-cycle dependent activation, and a set of genes coding for all four nucleosomal proteins. Mating type and a data yielded all of the four relevant DNA motifs and most of the known a- and -specific genes. REFERENCES
- Pennisi, E. 1997. Laboratory workhorse decoded. Science 277: 1432−1434. | Article | PubMed | ISI | ChemPort |
- Blattner, F.R., Plunkett, G., Bloch, C.A., Perna, N.T., Burland, V., Riley, M. et al. 1997. The complete genome sequence of Escherichla coli K-12. Science 277: 1453−1474. | Article | PubMed | ISI | ChemPort |
- Goffeau, A., Barrell, B.G., Bussey, H., Davis, R.W., Dujon, B., Feldman, H. et al. 1996. Life with 6000 genes. Science 274: 563−567. | Article |
- Chen, P., Ailion, M., Bobik, T., Stormo, G. and Roth, J. 1995. Five promoters integrate control of the cob/pdu regulon in Salmonella typhimurium. J. Bacteriol. 177: 5401−5410. | PubMed | ISI | ChemPort |
- Chuang, S.E., Daniels, D.L. and Blattner, F.R. 1993. Global regulation of gene expression in Escherichia coli. J. Bacteriol. 175: 2026−2036. | PubMed | ISI | ChemPort |
- Schena, M., Shalon, D., Davis, R.W. and Brown, P.O. 1995. Quantitative monitoring of gene expression patterns with a complementary DNA microarray. Science 270: 467−470. | PubMed | ISI | ChemPort |
- Lockhart, D.J., Dong, H.L., Byrne, M.C., Follettie, M.T., Gallo, M.V., Chee, M.S. et al. 1996. Expression monitoring by hybridization to high-density oligonucleotide arrays. Nat. Biotechnol. 14: 1675−1680. | PubMed | ISI | ChemPort |
- DeRisi, J., Penland L., Brown, P.O., Bittner, M.L., Mertzer, P.S., Ray, M. et al. 1996. Use of a cDNA microarray to analyse gene expression patterns in human cancer. Nat. Genet. 14: 457−460. | PubMed | ISI | ChemPort |
- Wodicka L., Dong, H., Mittmann, M., Ho, M.-H., and Lockhart, D.J. 1997. Genome-wide expression monitoring in Saccharomyces cerevisiae. Nat Biotechnol. 15: 1359−1366. | PubMed | ISI | ChemPort |
- Muhlrad, D., Decker, C.J. and Parker, R. 1995. Turnover mechanisms of the stable yeast PGK1 mRNA. Mol. Cell. Biol. 15: 2145−2156. | PubMed | ISI | ChemPort |
- Jacobson, A. and Peltz, S.W. 1996. Interrelationships of the pathways of mRNA decay and translation in eukaryotic cells. Annu. Rev. Biochem. 65: 693−739. | Article | PubMed | ISI | ChemPort |
- Lipman, D.J. 1997. Making (anti)sense of non-coding sequence conservation. Nucleic Acids. Res. 25: 3580−3583. | Article | PubMed | ISI | ChemPort |
- Freeh, K., Quandt, K. and Werner, T. 1997. Software for the analysis of DNA sequence elements of transcription. CABIOS 13: 89−97. | PubMed |
- Bailey, T.L. and Elkan, C. 1995. Unsupervised learning of multiple motifs in biopolymers using expectation maximization. Machine Learning Journal 21: 51−83. | Article |
- Neuwald, A.F., Liu, J.S. and Lawrence, C.E. 1995. Gibbs motif sampling: detection of bacterial outer membrane protein repeats. Protein Sci. 4: 1618−1632. | PubMed | ISI | ChemPort |
- Lawrence, C.E., Altschul, S.F., Boguski, M.S., Liu, J.S., Neuwald, A.F. and Wootton, J.C. 1993. Detecting subtle sequence signals: a Gibbs sampling strategy for multiple alignment. Science 262: 208−214. | PubMed | ISI | ChemPort |
- Lohr, D., Venkov, P. and Zlatanova, J. 1995. Transcriptional regulation in the yeast GAL gene family: a complex genetic network. FASEB J. 9: 777−787. | PubMed | ISI | ChemPort |
- Schneider, T.D. and Stephens, R.M. 1990. Sequence logos: a new way to display consensus sequences. Nucleic Acids Res. 18: 6097−6100. | PubMed | ISI | ChemPort |
- Freeman, K.B., Karns, L.R., Lutz, K.A. and Smith, M.M. 1992. Histone H3 transcription in Saccharomyces cerevisiae is controlled by multiple cell cycle activation sites and a constitutive negative regulatory element. Mol. Cell. Biol. 12: 5455−5463. | PubMed | ISI | ChemPort |
- Osley, M.A. 1991. The regulation of histone synthesis in the cell cycle. Annu. Rev. Biochem. 60: 827−861. | Article | PubMed | ISI | ChemPort |
- Breeden, L. 1996. Start-specific transcription in yeast. Curr. Top. Microbiol. Immunol. 208: 95−127. | PubMed | ISI | ChemPort |
- Mclnerny, C.J., Partridge, J.F., Mikesell, G.E., Creemer, D.P. and Breeden, L.L. 1997. A novel Mcm1-dependent element in the SWI4, CLN3, CDC6, and CDC47 promoters activates M/G1 -specific transcription. Genes Dev. 11: 1277−1288. | PubMed | ISI | ChemPort |
- Herskowitz, I., Rine, J. and Strathern, J. 1992. Mating-type determination and mating-type interconversion in Saccharomyces cerevisiae, pp. 583−656, in Gene expression, Vol. 2. Jones, E.W., Pringle, J.R., and Broach, J.R. (eds.). Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York.
- Johnston, M. and Carlson, M. 1992. Regulation of carbon and phosphate utilization, pp. 193−281 in Gene expression, Vol. 2. Jones, E.W., Pringle, J.R., and Broach, J.R. (eds.). Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York.
- Craig, E.A. 1992. The heat-shock response of Saccharomyces cerevisiae, pp. 501−537, in Gene expression, Vol. 2. Jones, E.W., Pringle, J.R., and Broach, J.R. (eds.). Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York.
- Schmitt, A.P. and McEntee, K., 1996. Msn2p, a zinc finger DNA-binding protein, is the transcriptional activator of the multistress response in Saccharomyces cerevisiae. Proc. Natl. Acad. Sci. USA 93: 5777−5782. | Article | PubMed | ChemPort |
- Rowley, A., Johnston, G.C., Butler, B., Wemer-Washburne, M. and Singer, R.A. 1993. Heat shock-mediated cell cycle blockage and G1 cyclin expression in the yeast Saccharomyces cerevisiae. Mol. Cell. Biol. 13: 1034−1041. | PubMed | ISI | ChemPort |
- Vashee, S., Xu, H., Johnston, S.A. and Kodadek, T. 1993. How do "Zn2 cys6" proteins distinguish between similar upstream activation sites? Comparison of the DNA-binding specificity of the GAL4 protein in vitro and in vivo. J. Biol. Chem. 268: 24699−24706. | PubMed | ISI | ChemPort |
- Cherry, J.M., Adler C., Ball, C., Chervitz, S.A., Dwight, S.S., Hester, E.T. et al. 1998. SGD: saccharomyces genome database. Nucleic Acids Res. 26: 73−79. | Article | PubMed | ISI | ChemPort |
- Ni, H.T. and LaPorte, D.C. 1995. Response of a yeast glycogen synthase gene to stress. Mol. Microbiol. 16: 1197−1205. | PubMed | ISI | ChemPort |
- Sprague, G.F. and Thorner, J.W. 1992. Pheromone response and signal transduction during the mating process of Saccharomyces cerevisiae, pp. 657−744, in Gene expression, Vol. 2. Jones, E.W., Pringle, J.R., and Broach, J.R. (eds.). Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York.
- Wen, X., Fuhrman, S., Michaels, G.S., Carr, D.B., Smith, S., Barker, J.L. et al. 1998. Large-scale temporal gene expression mapping of central nervous system development. Proc. Natl. Acad. Sci USA 95: 334−339. | Article | PubMed | ChemPort |
- Winston F., Dollard, C., and Ricupero-Hovasse, S.L. 1995. Construction of a set of convenient Saccharomyces cerevisiae strains that are isogenic to S288C. Yeast 11 53−55. | PubMed | ISI | ChemPort |
- Goffeau, A., Barrell, B.G., Bussey, H., Davis, R.W., Dujon, B. et al. 1996. Life with 6000 genes. Science 274: 563−567. | Article |
- Miller, M.J., Xuong, N.H. and Geiduschek, E.P. 1982. Quantitative analysis of the heat shock response of Saccharomyces cerevisiae. J. Bacteriol. 151: 311−327. | PubMed | ISI | ChemPort |
- Wenzel, T.J., Teunissen, A.W., and de Steensma, H.Y. 1995. PDA1 mRNA: a standard for quantitation of mRNA in Saccharomyces cerevisiae superior to ACT1 mRNA. Nucleic Acids Res. 23: 883−884. | PubMed | ISI | ChemPort |
- Berg, O.G. and von Hippel, P.H. 1987. Selection of DNA binding sites by regulatory proteins. Statistical-mechanical theory and application to operators and promoters. J. Mol. Biol. 193: 723−750. | PubMed | ISI | ChemPort |
- Liu, J.S., Neuwald, A.F, and Lawrence, C.E. 1995. Bayesian models for multiple local sequence alignment and Gibbs sampling strategies. J. Amen Stat Assoc. 90: 1156−1170.
- http://arep.med.harvard.edu/mrnadata
- Wingender, E., Kel, A.E., Kel, O.V., Karas, H., Heinemeyer, T. et al. 1997. TRANSFAC, TRRD and COMPEL: towards a federated database system on transcriptional regulation. Nucleic Acids Res. 25: 265−268. | Article | PubMed | ISI | ChemPort |
- Quandt, K., Frech, K., Karas, H., Wingender, E. and Werner, T. 1995. MatInd and matInspector: new fast and versatile tools for detection of consensus matches in nucleotide sequence data. Nucleic Acids Res. 23: 4878−4884. | PubMed | ISI | ChemPort |
- Simon J.A. and Lis, J.T. 1987. A germline transformation analysis reveals flexibility in the organization of heat shock consensus elements. Nucleic Acids Res. 15: 5971−2988.
- Schuller C., Brewster, J.L., Alexander, M.R., Gustin, M.C., and Ruis, H. 1994. The HOG pathway controls osmotic regulation of transcription via the stress response element (STRE) of the Saccharomyces cerevisiae CTT1 gene. EMBO J. 13: 4382−4389. | PubMed | ISI | ChemPort |
- Martinez-Pastor, M.T., Marchler, G., Schuller, C., Marchler-Bauer, A., Ruis, H. et al. 1996. The Saccharomyces cerevisiae zinc finger proteins Msn2p and Msn4p are required for transcriptional induction through the stress response element (STRE). EMBO J. 15: 2227−2235. | PubMed | ISI | ChemPort |
- Tavazoie, S. and Church, G.M. 1998. Quantitative whole-genome analysis of DNA-protein interactions by in vivo methylase protection in E. coli. Nat. Biotechnol. 16: 566−571. | Article | PubMed | ISI | ChemPort |
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