Quantitative inference of dynamic regulatory pathways via microarray data.
BACKGROUND
The cellular signaling pathway (network) is one of the main topics of organismic investigations. The intracellular interactions between genes in a signaling pathway are considered as the foundation of functional genomics. Thus, what genes and how much they influence each other through transcriptional binding or physical interactions are essential problems. Under the synchronous measures of gene expression via a microarray chip, an amount of dynamic information is embedded and remains to be discovered. Using a systematically dynamic modeling approach, we explore the causal relationship among genes in cellular signaling pathways from the system biology approach.


RESULTS
In this study, a second-order dynamic model is developed to describe the regulatory mechanism of a target gene from the upstream causality point of view. From the expression profile and dynamic model of a target gene, we can estimate its upstream regulatory function. According to this upstream regulatory function, we would deduce the upstream regulatory genes with their regulatory abilities and activation delays, and then link up a regulatory pathway. Iteratively, these regulatory genes are considered as target genes to trace back their upstream regulatory genes. Then we could construct the regulatory pathway (or network) to the genome wide. In short, we can infer the genetic regulatory pathways from gene-expression profiles quantitatively, which can confirm some doubted paths or seek some unknown paths in a regulatory pathway (network). Finally, the proposed approach is validated by randomly reshuffling the time order of microarray data.


CONCLUSIONS
We focus our algorithm on the inference of regulatory abilities of the identified causal genes, and how much delay before they regulate the downstream genes. With this information, a regulatory pathway would be built up using microarray data. In the present study, two signaling pathways, i.e. circadian regulatory pathway in Arabidopsis thaliana and metabolic shift pathway from fermentation to respiration in yeast Saccharomyces cerevisiae, are reconstructed using microarray data to evaluate the performance of our proposed method. In the circadian regulatory pathway, we identified mainly the interactions between the biological clock and the photoperiodic genes consistent with the known regulatory mechanisms. We also discovered the now less-known regulations between crytochrome and phytochrome. In the metabolic shift pathway, the casual relationship of enzymatic genes could be detected properly.
Chang
Wen-Chieh
WC
Lab. of System Biology, National Tsing Hua University, 101, Sec 2, Kuang Fu Road, Hsinchu, 300, Taiwan. cwli@moti.ee.nthu.edu.tw <cwli@moti.ee.nthu.edu.tw>
Li
Chang-Wei
CW
Chen
Bor-Sen
BS
D000465:Algorithms; D017360:Arabidopsis / Q000378:metabolism; D002940:Circadian Rhythm; D019295:Computational Biology / Q000295:instrumentation / Q000379:methods*; D003198:Computer Simulation; D004268:DNA-Binding Proteins; D005285:Fermentation; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D015966:Gene Expression Regulation, Fungal; D005800:Genes, Fungal; D017343:Genes, Plant; D016681:Genome, Fungal; D016013:Likelihood Functions; D008954:Models, Biological; D015233:Models, Statistical; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods*; D011485:Protein Binding; D025941:Protein Interaction Mapping / Q000379:methods*; D012441:Saccharomyces cerevisiae / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000737:chemistry; D015398:Signal Transduction; D014157:Transcription Factors
D004268:DNA-Binding Proteins; D029701:Saccharomyces cerevisiae Proteins; D014157:Transcription Factors