Computational reconstruction of transcriptional regulatory modules of the yeast cell cycle

Integrating gene expression and ChIP-chip data, we develop a method, called MOdule Finding Algorithm (MOFA), for reconstructing TRMs of the yeast cell cycle. MOFA identified 87 TRMs, which together contain 336 distinct genes regulated by 40 TFs. Using various kinds of data, we validated the biological relevance of the identified TRMs. Our analysis shows that different combinations of a fairly small number of TFs are responsible for regulating a large number of genes involved in different cell cycle phases and that there may exist crosstalk between the cell cycle and other cellular processes. MOFA is capable of finding many novel TF-target gene relationships and can determine whether a TF is an activator or/and a repressor. Finally, MOFA refines some clusters proposed by previous studies and provides a better understanding of how the complex expression program of the cell cycle is regulated.MOFA was developed to reconstruct TRMs of the yeast cell cycle. Many of these TRMs are in agreement with previous studies. Further, MOFA inferred many interesting modules and novel TF combinations. We believe that computational analysis of multiple types of data will be a powerful approach to studying complex biological systems when more and more genomic resources such as genome-wide protein activity data and protein-protein interaction data become available.A transcriptional regulatory module (TRM) is a set of genes that is regulated by a common set of TFs. By organizing the genome into TRMs, a living cell can coordinate the activities of many genes and carry out complex functions. Therefore, identifying TRMs is useful for understanding cellular responses to internal and external signals. The advances of high-throughput genomic tools such as DNA microarray [1,2] and chromatin immunoprecipitation-DNA chip (ChIP-chip) [3,4] have made the computational reconstruction of TRMs of a eukaryotic cell possible.Genome-wide gene expression analysis has been used to investigate TRMs controll