title: Computational gene network analysis reveals TNF-induced angiogenesis.
abstract: BACKGROUND
  TNF (Tumor Necrosis Factor-α) induces HUVEC (Human Umbilical Vein Endothelial Cells) to proliferate and form new blood vessels. This TNF-induced angiogenesis plays a key role in cancer and rheumatic disease. However, the molecular system that underlies TNF-induced angiogenesis is largely unknown.
  
  
  METHODS
  We analyzed the gene expression changes stimulated by TNF in HUVEC over a time course using microarrays to reveal the molecular system underlying TNF-induced angiogenesis. Traditional k-means clustering analysis was performed to identify informative temporal gene expression patterns buried in the time course data. Functional enrichment analysis using DAVID was then performed for each cluster. The genes that belonged to informative clusters were then used as the input for gene network analysis using a Bayesian network and nonparametric regression method. Based on this TNF-induced gene network, we searched for sub-networks related to angiogenesis by integrating existing biological knowledge.
  
  
  RESULTS
  k-means clustering of the TNF stimulated time course microarray gene expression data, followed by functional enrichment analysis identified three biologically informative clusters related to apoptosis, cellular proliferation and angiogenesis. These three clusters included 648 genes in total, which were used to estimate dynamic Bayesian networks. Based on the estimated TNF-induced gene networks, we hypothesized that a sub-network including IL6 and IL8 inhibits apoptosis and promotes TNF-induced angiogenesis. More particularly, IL6 promotes TNF-induced angiogenesis by inducing NF-κB and IL8, which are strong cell growth factors.
  
  
  CONCLUSIONS
  Computational gene network analysis revealed a novel molecular system that may play an important role in the TNF-induced angiogenesis seen in cancer and rheumatic disease. This analysis suggests that Bayesian network analysis linked to functional annotation may be a powerful tool to provide insight into disease.
authors.affiliation: Human Genome Center, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639 Japan.
authors.forename: Kentaro
authors.initials: K
authors.lastname: Ogami
authors.forename: Rui
authors.initials: R
authors.lastname: Yamaguchi
authors.forename: Seiya
authors.initials: S
authors.lastname: Imoto
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Tamada
authors.forename: Hiromitsu
authors.initials: H
authors.lastname: Araki
authors.forename: Cristin
authors.initials: C
authors.lastname: Print
authors.forename: Satoru
authors.initials: S
authors.lastname: Miyano
mesh_terms: D001499:Bayes Theorem; D014408:Biomarkers, Tumor / Q000235:genetics; D016000:Cluster Analysis; D019295:Computational Biology / Q000379:methods*; D053263:Gene Regulatory Networks; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D018919:Neovascularization, Physiologic / Q000187:drug effects* / Q000235:genetics*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
chemical_list: D014408:Biomarkers, Tumor; D014409:Tumor Necrosis Factor-alpha