title: Applying attractor dynamics to infer gene regulatory interactions involved in cellular differentiation.
abstract: The dynamics of gene regulatory networks (GRNs) guide cellular differentiation. Determining the ways regulatory genes control expression of their targets is essential to understand and control cellular differentiation. The way a regulatory gene controls its target can be expressed as a gene regulatory function. Manual derivation of these regulatory functions is slow, error-prone and difficult to update as new information arises. Automating this process is a significant challenge and the subject of intensive effort. This work presents a novel approach to discovering biologically plausible gene regulatory interactions that control cellular differentiation. This method integrates known cell type expression data, genetic interactions, and knowledge of the effects of gene knockouts to determine likely GRN regulatory functions. We employ a genetic algorithm to search for candidate GRNs that use a set of transcription factors that control differentiation within a lineage. Nested canalyzing functions are used to constrain the search space to biologically plausible networks. The method identifies an ensemble of GRNs whose dynamics reproduce the gene expression pattern for each cell type within a particular lineage. The method's effectiveness was tested by inferring consensus GRNs for myeloid and pancreatic cell differentiation and comparing the predicted gene regulatory interactions to manually derived interactions. We identified many regulatory interactions reported in the literature and also found differences from published reports. These discrepancies suggest areas for biological studies of myeloid and pancreatic differentiation. We also performed a study that used defined synthetic networks to evaluate the accuracy of the automated search method and found that the search algorithm was able to discover the regulatory interactions in these defined networks with high accuracy. We suggest that the GRN functions derived from the methods described here can be used to fill gaps in knowledge about regulatory interactions and to offer hypotheses for experimental testing of GRNs that control differentiation and other biological processes.
authors.affiliation: Computer Science Department, Utah State University, 4205 Old Main Hill, Logan, UT 84322, United States. Electronic address: ghaffarizadeh@aggiemail.usu.edu.
authors.forename: Ahmadreza
authors.initials: A
authors.lastname: Ghaffarizadeh
authors.affiliation: Biology Department, Utah State University, 5305 Old Main Hill, Logan, UT 84322, United States; Center for Integrated BioSystems, 4700 Old Main Hill, Logan, UT 84322, United States. Electronic address: greg.podgorski@usu.edu.
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Podgorski
authors.affiliation: Computer Science Department, Utah State University, 4205 Old Main Hill, Logan, UT 84322, United States; Institute for Systems Biology, 401 Terry Ave N, Seattle, WA 98109, United States; Synthetic Biomanufacturing Institute, 1780 N. Research Park Way, Suite 108, North Logan, UT 84341, United States. Electronic address: nick.flann@usu.edu.
authors.forename: Nicholas S
authors.initials: NS
authors.lastname: Flann
mesh_terms: D000465:Algorithms; D000818:Animals; D002454:Cell Differentiation / Q000235:genetics*; D019070:Cell Lineage / Q000235:genetics; D019295:Computational Biology / Q000379:methods*; D003198:Computer Simulation; D020869:Gene Expression Profiling / Q000379:methods*; D053263:Gene Regulatory Networks / Q000235:genetics*; D006801:Humans; D008957:Models, Genetic; D022423:Myeloid Cells / Q000166:cytology / Q000378:metabolism; D010179:Pancreas / Q000166:cytology / Q000378:metabolism; D060066:Protein Interaction Maps / Q000235:genetics*; D015203:Reproducibility of Results; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D014157:Transcription Factors
keywords: Attractor dynamics; Gene regulatory networks; Genetic algorithm; Nested canalyzing functions