title: Reconstructing directed gene regulatory network by only gene expression data.
abstract: Accurately identifying gene regulatory network is an important task in understanding in vivo biological activities. The inference of such networks is often accomplished through the use of gene expression data. Many methods have been developed to evaluate gene expression dependencies between transcription factor and its target genes, and some methods also eliminate transitive interactions. The regulatory (or edge) direction is undetermined if the target gene is also a transcription factor. Some methods predict the regulatory directions in the gene regulatory networks by locating the eQTL single nucleotide polymorphism, or by observing the gene expression changes when knocking out/down the candidate transcript factors; regrettably, these additional data are usually unavailable, especially for the samples deriving from human tissues.
  
  
  
  In this study, we propose the Context Based Dependency Network (CBDN), a method that is able to infer gene regulatory networks with the regulatory directions from gene expression data only. To determine the regulatory direction, CBDN computes the influence of source to target by evaluating the magnitude changes of expression dependencies between the target gene and the others with conditioning on the source gene. CBDN extends the data processing inequality by involving the dependency direction to distinguish between direct and transitive relationship between genes. We also define two types of important regulators which can influence a majority of the genes in the network directly or indirectly. CBDN can detect both of these two types of important regulators by averaging the influence functions of candidate regulator to the other genes. In our experiments with simulated and real data, even with the regulatory direction taken into account, CBDN outperforms the state-of-the-art approaches for inferring gene regulatory network. CBDN identifies the important regulators in the predicted network: 1. TYROBP influences a batch of genes that are related to Alzheimer's disease; 2. ZNF329 and RB1 significantly regulate those 'mesenchymal' gene expression signature genes for brain tumors.
  
  
  
  By merely leveraging gene expression data, CBDN can efficiently infer the existence of gene-gene interactions as well as their regulatory directions. The constructed networks are helpful in the identification of important regulators for complex diseases.
authors.affiliation: Department of Computer Science, City University of Hong Kong, Kowloon, Hong Kong.
authors.forename: Lu
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Computer Science, City University of Hong Kong, Kowloon, Hong Kong.
authors.forename: Xi Kang
authors.initials: XK
authors.lastname: Feng
authors.affiliation: Faculty of Information and Communication Technology, University Tunku Abdul Rahman, Kampar, Perak, Malaysia.
authors.forename: Yen Kaow
authors.initials: YK
authors.lastname: Ng
authors.affiliation: Department of Computer Science, City University of Hong Kong, Kowloon, Hong Kong. shuaicli@gmail.com.
authors.forename: Shuai Cheng
authors.initials: SC
authors.lastname: Li
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000465:Algorithms; D000544:Alzheimer Disease / Q000235:genetics*; D001921:Brain / Q000378:metabolism / Q000473:pathology; D019295:Computational Biology; D003198:Computer Simulation; D004268:DNA-Binding Proteins / Q000235:genetics*; D005786:Gene Expression Regulation / Q000235:genetics; D053263:Gene Regulatory Networks / Q000235:genetics; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci / Q000235:genetics; D056286:Retinoblastoma Binding Proteins / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics; D059467:Transcriptome; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D004268:DNA-Binding Proteins; D008565:Membrane Proteins; C000606393:RB1 protein, human; D056286:Retinoblastoma Binding Proteins; C110546:TYROBP protein, human; D014157:Transcription Factors; C435644:ZNF330 protein, human; D044767:Ubiquitin-Protein Ligases
keywords: Gene expression; Gene regulatory network; Important regulators; Regulatory direction