Quantitative characterization of the transcriptional regulatory network in the yeast cell cycle

MOTIVATION Genome-wide gene expression programs have been monitored and analyzed in the yeast Saccharomyces cerevisiae, but how cells regulate global gene expression programs in response to environmental changes is still far from being understood. We present a systematic approach to quantitatively characterize the transcriptional regulatory network of the yeast cell cycle. For the interpretative purpose, 20 target genes were selected because their expression patterns fluctuated in a periodic manner concurrent with the cell cycle and peaked at different phases. In addition to the most significant five possible regulators of each specific target gene, the expression pattern of each target gene affected by synergy of the regulators during the cell cycle was characterized. Our first step includes modeling the dynamics of gene expression and extracting the transcription rate from a time-course microarray data. The second step embraces finding the regulators that possess a high correlation with the transcription rate of the target gene, and quantifying the regulatory abilities of the identified regulators. RESULTS Our network discerns not only the role of the activator or repressor for each specific regulator, but also the regulatory ability of the regulator to the transcription rate of the target gene. The highly coordinated regulatory network has identified a group of significant regulators responsible for the gene expression program through the cell cycle progress. This approach may be useful for computing the regulatory ability of the transcriptional regulatory networks in more diverse conditions and in more complex eukaryotes. SUPPLEMENTARY INFORMATION Matlab code and test data are available at http://www.ee.nthu.edu.tw/~bschen/quantitative/regulatory_network.htm

[1]  N. Camougrand,et al.  The SUN family of Saccharomyces cerevisiae: the double knock-out of UTH1 and SIM1 promotes defects in nucleus migration and increased drug sensitivity. , 2000, FEMS microbiology letters.

[2]  B. Futcher.  Transcriptional regulatory networks and the yeast cell cycle. , 2002, Current opinion in cell biology.

[3]  Michael Ruogu Zhang,et al.  Comprehensive identification of cell cycle-regulated genes of the yeast Saccharomyces cerevisiae by microarray hybridization. , 1998, Molecular biology of the cell.

[4]  Kim Nasmyth,et al.  The B-type cyclin kinase inhibitor p40 SIC1 controls the G1 to S transition in S. cerevisiae , 1994, Cell.

[5]  L. Breeden,et al.  A novel Mcm1-dependent element in the SWI4, CLN3, CDC6, and CDC47 promoters activates M/G1-specific transcription. , 1997, Genes & development.

[6]  Jesper Tegnér,et al.  Reverse engineering gene networks using singular value decomposition and robust regression , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[7]  G. Church,et al.  Systematic determination of genetic network architecture , 1999, Nature Genetics.

[8]  R. Singer,et al.  Messenger RNA in HeLa cells: kinetics of formation and decay. , 1973, Journal of molecular biology.

[9]  D. Koshland,et al.  An amplified sensitivity arising from covalent modification in biological systems. , 1981, Proceedings of the National Academy of Sciences of the United States of America.

[10]  B. Futcher,et al.  Comparison of the Saccharomyces cerevisiae G1 cyclins: Cln3 may be an upstream activator of Cln1, Cln2 and other cyclins. , 1993, The EMBO journal.

[11]  M. Gerstein,et al.  Complex transcriptional circuitry at the G1/S transition in Saccharomyces cerevisiae. , 2002, Genes & development.

[12]  Richard A Young,et al.  Deciphering gene expression regulatory networks. , 2002, Current opinion in genetics & development.

[13]  Bruce Futcher,et al.  The G1 Cyclin Cln3 Promotes Cell Cycle Entry via the Transcription Factor Swi6 , 2002, Molecular and Cellular Biology.

[14]  C. Garvie,et al.  Recognition of specific DNA sequences. , 2001, Molecular cell.

[15]  T. Mestl,et al.  A mathematical framework for describing and analysing gene regulatory networks. , 1995, Journal of theoretical biology.

[16]  G. Church,et al.  Identifying regulatory networks by combinatorial analysis of promoter elements , 2001, Nature Genetics.

[17]  D. Botstein,et al.  Singular value decomposition for genome-wide expression data processing and modeling. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[18]  Ronald W. Davis,et al.  A genome-wide transcriptional analysis of the mitotic cell cycle. , 1998, Molecular cell.

[19]  Stephen S. Gisselbrecht,et al.  Ras Pathway Specificity Is Determined by the Integration of Multiple Signal-Activated and Tissue-Restricted Transcription Factors , 2000, Cell.

[20]  Angelika Amon,et al.  Separase, Polo Kinase, the Kinetochore Protein Slk19, and Spo12 Function in a Network that Controls Cdc14 Localization during Early Anaphase , 2002, Cell.

[21]  T. Kunoh,et al.  YHP1 encodes a new homeoprotein that binds to the IME1 promoter in Saccharomyces cerevisiae , 2000, Yeast.

[22]  J. Mesirov,et al.  Interpreting patterns of gene expression with self-organizing maps: methods and application to hematopoietic differentiation. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[23]  K. Nasmyth,et al.  Whose end is destruction: cell division and the anaphase-promoting complex. , 1999, Genes & development.

[24]  Nicola J. Rinaldi,et al.  Transcriptional Regulatory Networks in Saccharomyces cerevisiae , 2002, Science.

[25]  C. Wittenberg,et al.  CLN3, not positive feedback, determines the timing of CLN2 transcription in cycling cells. , 1995, Genes & development.

[26]  P. Roach,et al.  The yeast cyclins Pc16p and Pc17p are involved in the control of glycogen storage by the cyclin‐dependent protein kinase Pho85p , 2001, FEBS letters.

[27]  John D. Storey,et al.  Precision and functional specificity in mRNA decay , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[28]  Michael Q. Zhang,et al.  Functional genomics as applied to mapping transcription regulatory networks. , 2002, Current opinion in microbiology.

[29]  D. Botstein,et al.  Cluster analysis and display of genome-wide expression patterns. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[30]  D. Botstein,et al.  Genomic binding sites of the yeast cell-cycle transcription factors SBF and MBF , 2001, Nature.

[31]  Neal S. Holter,et al.  Dynamic modeling of gene expression data. , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[32]  John G. Proakis,et al.  Digital Communications , 1983 .

[33]  H. Bussemaker,et al.  Regulatory element detection using correlation with expression , 2001, Nature Genetics.

[34]  P. Woolf,et al.  A fuzzy logic approach to analyzing gene expression data. , 2000, Physiological genomics.

[35]  Nicola J. Rinaldi,et al.  Serial Regulation of Transcriptional Regulators in the Yeast Cell Cycle , 2001, Cell.

[36]  Gary D. Stormo,et al.  Identifying target sites for cooperatively binding factors , 2001, Bioinform..

[37]  Lukas Endler,et al.  Forkhead-like transcription factors recruit Ndd1 to the chromatin of G2/M-specific promoters , 2000, Nature.

[38]  Attila Tóth,et al.  Division of the nucleolus and its release of CDC14 during anaphase of meiosis I depends on separase, SPO12, and SLK19. , 2003, Developmental cell.

[39]  Angelika Amon,et al.  The Cdc14 phosphatase and the FEAR network control meiotic spindle disassembly and chromosome segregation. , 2003, Developmental cell.

[40]  G. Orphanides,et al.  A Unified Theory of Gene Expression , 2002, Cell.

[41]  Terence Hwa,et al.  Extracting transcriptional events from temporal gene expression patterns during Dictyostelium development , 2002, Bioinform..

[42]  Katherine C. Chen,et al.  Kinetic analysis of a molecular model of the budding yeast cell cycle. , 2000, Molecular biology of the cell.

[43]  Hongquan Xu,et al.  A smooth response surface algorithm for constructing a gene regulatory network. , 2002, Physiological genomics.

[44]  J. Fickett,et al.  Discovery and modeling of transcriptional regulatory regions. , 2000, Current opinion in biotechnology.

[45]  D. Botstein,et al.  Two yeast forkhead genes regulate the cell cycle and pseudohyphal growth , 2000, Nature.

[46]  M. Kirschner,et al.  Properties of Saccharomyces cerevisiae wee1 and its differential regulation of p34CDC28 in response to G1 and G2 cyclins. , 1993, The EMBO journal.

[47]  H. Akaike.  A new look at the statistical model identification , 1974 .

[48]  S. Carr,et al.  Phosphorylation of Sic1p by G1 Cdk required for its degradation and entry into S phase. , 1997, Science.