title: A Generalized Gene-Regulatory Network Model of Stem Cell Differentiation for Predicting Lineage Specifiers.
abstract: Identification of cell-fate determinants for directing stem cell differentiation remains a challenge. Moreover, little is known about how cell-fate determinants are regulated in functionally important subnetworks in large gene-regulatory networks (i.e., GRN motifs). Here we propose a model of stem cell differentiation in which cell-fate determinants work synergistically to determine different cellular identities, and reside in a class of GRN motifs known as feedback loops. Based on this model, we develop a computational method that can systematically predict cell-fate determinants and their GRN motifs. The method was able to recapitulate experimentally validated cell-fate determinants, and validation of two predicted cell-fate determinants confirmed that overexpression of ESR1 and RUNX2 in mouse neural stem cells induces neuronal and astrocyte differentiation, respectively. Thus, the presented GRN-based model of stem cell differentiation and computational method can guide differentiation experiments in stem cell research and regenerative medicine.
authors.affiliation: Computational Biology Group, Luxembourg Centre for Systems Biomedicine, University of Luxembourg, 7 Avenue des Hauts Fourneaux, 4362 Esch-sur-Alzette, Luxembourg.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Okawa
authors.affiliation: Developmental and Cellular Biology Group, Luxembourg Centre for Systems Biomedicine, University of Luxembourg, 7 Avenue des Hauts Fourneaux, 4362 Esch-sur-Alzette, Luxembourg.
authors.forename: Sarah
authors.initials: S
authors.lastname: Nicklas
authors.affiliation: Computational Biology Group, Luxembourg Centre for Systems Biomedicine, University of Luxembourg, 7 Avenue des Hauts Fourneaux, 4362 Esch-sur-Alzette, Luxembourg.
authors.forename: Sascha
authors.initials: S
authors.lastname: Zickenrott
authors.affiliation: Developmental and Cellular Biology Group, Luxembourg Centre for Systems Biomedicine, University of Luxembourg, 7 Avenue des Hauts Fourneaux, 4362 Esch-sur-Alzette, Luxembourg.
authors.forename: Jens C
authors.initials: JC
authors.lastname: Schwamborn
authors.affiliation: Computational Biology Group, Luxembourg Centre for Systems Biomedicine, University of Luxembourg, 7 Avenue des Hauts Fourneaux, 4362 Esch-sur-Alzette, Luxembourg. Electronic address: antonio.delsol@uni.lu.
authors.forename: Antonio
authors.initials: A
authors.lastname: Del Sol
mesh_terms: D000465:Algorithms; D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics*; D019070:Cell Lineage / Q000235:genetics*; D019295:Computational Biology / Q000379:methods; D003198:Computer Simulation; D050659:Core Binding Factor Alpha 1 Subunit / Q000378:metabolism; D030541:Databases, Genetic; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism; D047628:Estrogen Receptor alpha / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D053263:Gene Regulatory Networks; D051379:Mice; D008954:Models, Biological; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology* / Q000378:metabolism*
chemical_list: D050659:Core Binding Factor Alpha 1 Subunit; D047628:Estrogen Receptor alpha