title: Modeling dynamic functional relationship networks and application to ex vivo human erythroid differentiation.
abstract: BACKGROUND
  Functional relationship networks, which summarize the probability of co-functionality between any two genes in the genome, could complement the reductionist focus of modern biology for understanding diverse biological processes in an organism. One major limitation of the current networks is that they are static, while one might expect functional relationships to consistently reprogram during the differentiation of a cell lineage. To address this potential limitation, we developed a novel algorithm that leverages both differentiation stage-specific expression data and large-scale heterogeneous functional genomic data to model such dynamic changes. We then applied this algorithm to the time-course RNA-Seq data we collected for ex vivo human erythroid cell differentiation.
  
  
  RESULTS
  Through computational cross-validation and literature validation, we show that the resulting networks correctly predict the (de)-activated functional connections between genes during erythropoiesis. We identified known critical genes, such as HBD and GATA1, and functional connections during erythropoiesis using these dynamic networks, while the traditional static network was not able to provide such information. Furthermore, by comparing the static and the dynamic networks, we identified novel genes (such as OSBP2 and PDZK1IP1) that are potential drivers of erythroid cell differentiation. This novel method of modeling dynamic networks is applicable to other differentiation processes where time-course genome-scale expression data are available, and should assist in generating greater understanding of the functional dynamics at play across the genome during development.
  
  
  METHODS
  The network described in this article is available at http://guanlab.ccmb.med.umich.edu/stageSpecificNetwork.
authors.affiliation: Department of Computational Medicine and Bioinformatics, Department of Cell and Developmental Biology, Department of Internal Medicine and Department of Computer Science and Engineering, University of Michigan, MI48109, USA.
authors.forename: Fan
authors.initials: F
authors.lastname: Zhu
authors.affiliation: Department of Computational Medicine and Bioinformatics, Department of Cell and Developmental Biology, Department of Internal Medicine and Department of Computer Science and Engineering, University of Michigan, MI48109, USA.
authors.forename: Lihong
authors.initials: L
authors.lastname: Shi
authors.affiliation: Department of Computational Medicine and Bioinformatics, Department of Cell and Developmental Biology, Department of Internal Medicine and Department of Computer Science and Engineering, University of Michigan, MI48109, USA.
authors.forename: Hongdong
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Computational Medicine and Bioinformatics, Department of Cell and Developmental Biology, Department of Internal Medicine and Department of Computer Science and Engineering, University of Michigan, MI48109, USA.
authors.forename: Ridvan
authors.initials: R
authors.lastname: Eksi
authors.affiliation: Department of Computational Medicine and Bioinformatics, Department of Cell and Developmental Biology, Department of Internal Medicine and Department of Computer Science and Engineering, University of Michigan, MI48109, USA.
authors.forename: James Douglas
authors.initials: JD
authors.lastname: Engel
authors.affiliation: Department of Computational Medicine and Bioinformatics, Department of Cell and Developmental Biology, Department of Internal Medicine and Department of Computer Science and Engineering, University of Michigan, MI48109, USA Department of Computational Medicine and Bioinformatics, Department of Cell and Developmental Biology, Department of Internal Medicine and Department of Computer Science and Engineering, University of Michigan, MI48109, USA Department of Computational Medicine and Bioinformatics, Department of Cell and Developmental Biology, Department of Internal Medicine and Department of Computer Science and Engineering, University of Michigan, MI48109, USA.
authors.forename: Yuanfang
authors.initials: Y
authors.lastname: Guan
mesh_terms: D000465:Algorithms; D004920:Erythropoiesis / Q000235:genetics*; D053263:Gene Regulatory Networks; D006801:Humans; D008957:Models, Genetic; D017423:Sequence Analysis, RNA; D059467:Transcriptome