title: Identifying responsive modules by mathematical programming: an application to budding yeast cell cycle.
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.
authors: Key Laboratory of Systems Biology, SIBS-Novo Nordisk Translational Research Centre for PreDiabetes, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
authors: Zhenshu
authors: Z
authors: Wen
authors: Zhi-Ping
authors: ZP
authors: Liu
authors: Yiqing
authors: Y
authors: Yan
authors: Guanying
authors: G
authors: Piao
authors: Zhengrong
authors: Z
authors: Liu
authors: Jiarui
authors: J
authors: Wu
authors: Luonan
authors: L
authors: Chen
mesh_terms: D015415:Biomarkers / Q000378:metabolism; D002453:Cell Cycle; D016000:Cluster Analysis; D005800:Genes, Fungal / Q000235:genetics; D008954:Models, Biological; D010641:Phenotype; D012441:Saccharomyces cerevisiae / Q000166:cytology* / Q000235:genetics / Q000378:metabolism; D049490:Systems Biology / Q000379:methods*
chemical_list: D015415:Biomarkers