Abstract
High-throughput biological data offer an unprecedented opportunity to fully characterize biological processes. However, how to extract meaningful biological information from these datasets is a significant challenge. Recently, pathway-based analysis has gained much progress in identifying biomarkers for some phenotypes. Nevertheless, these so-called pathway-based methods are mainly individual-gene-based or molecule-complex-based analyses. In this paper, we developed a novel module-based method to reveal causal or dependent relations between network modules and biological phenotypes by integrating both gene expression data and protein-protein interaction network. Specifically, we first formulated the identification problem of the responsive modules underlying biological phenotypes as a mathematical programming model by exploiting phenotype difference, which can also be viewed as a multi-classification problem. Then, we applied it to study cell-cycle process of budding yeast from microarray data based on our biological experiments, and identified important phenotype- and transition-based responsive modules for different stages of cell-cycle process. The resulting responsive modules provide new insight into the regulation mechanisms of cell-cycle process from a network viewpoint. Moreover, the identification of transition modules provides a new way to study dynamical processes at a functional module level. In particular, we found that the dysfunction of a well-known module and two new modules may directly result in cell cycle arresting at S phase. In addition to our biological experiments, the identified responsive modules were also validated by two independent datasets on budding yeast cell cycle.
Highlights
High-throughput biological technologies allow the simultaneous measurement of the expression of thousands of genes or proteins, which offers an unprecedented opportunity to fully characterize biological processes [1]
By integrating high-throughput gene expression data and protein-protein interaction (PPI) network, we developed a novel method to identify responsive modules and dynamical transition modules for various phenotypes and phase transitions under internal and external stimulus of yeast cell cycle process
We found that, compared to MIPS, these two databases contain more interactions, the overlap between MIPS and IntAct is relatively small
Summary
High-throughput biological technologies allow the simultaneous measurement of the expression of thousands of genes or proteins, which offers an unprecedented opportunity to fully characterize biological processes [1]. Gene-set-based or pathway-based analysis has been extended to perform classification of microarray data by exploiting the phenotype difference [19,20,21] and a number of approaches have been demonstrated for not scoring known pathways but extracting relevant sub-networks based on coherent expression patterns of the corresponding genes in the protein-protein interaction (PPI) networks [22,23,24,25]. In biology, a complex is a cluster of genes or proteins so closely related that they intergrade [26], while a pathway is a group of genes or proteins that are interacted (or related) [1]
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