title: Mathematical model of a gene regulatory network reconciles effects of genetic perturbations on hematopoietic stem cell emergence.
abstract: Interlinked gene regulatory networks (GRNs) are vital for the spatial and temporal control of gene expression during development. The hematopoietic transcription factors (TFs) Scl, Gata2 and Fli1 form one such densely connected GRN which acts as a master regulator of embryonic hematopoiesis. This triad has been shown to direct the specification of the hemogenic endothelium and emergence of hematopoietic stem cells (HSCs) in response to Notch1 and Bmp4-Smad signaling. Here we employ previously published data to construct a mathematical model of this GRN network and use this model to systematically investigate the network dynamical properties. Our model uses a statistical-thermodynamic framework to describe the combinatorial regulation of gene expression and reconciles, mechanistically, several previously published but unexplained results from different genetic perturbation experiments. In particular, our results demonstrate how the interactions of Runx1, an essential hematopoietic TF, with components of the Bmp4 signaling pathway allow it to affect triad activation and acts as a key regulator of HSC emergence. We also explain why heterozygous deletion of this essential TF, Runx1, speeds up the network dynamics leading to accelerated HSC emergence. Taken together our results demonstrate that the triad, a master-level controller of definitive hematopoiesis, is an irreversible bistable switch whose dynamical properties are modulated by Runx1 and components of the Bmp4 signaling pathway.
authors.affiliation: Department of Bioengineering, Rice University, Houston, TX, USA.
authors.forename: Jatin
authors.initials: J
authors.lastname: Narula
authors.forename: C J
authors.initials: CJ
authors.lastname: Williams
authors.forename: Abhinav
authors.initials: A
authors.lastname: Tiwari
authors.forename: Jonathon
authors.initials: J
authors.lastname: Marks-Bluth
authors.forename: John E
authors.initials: JE
authors.lastname: Pimanda
authors.forename: Oleg A
authors.initials: OA
authors.lastname: Igoshin
mesh_terms: D000818:Animals; D055415:Bone Morphogenetic Protein 4 / Q000378:metabolism; D003198:Computer Simulation; D050676:Core Binding Factor Alpha 2 Subunit / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental / Q000235:genetics / Q000502:physiology*; D053263:Gene Regulatory Networks / Q000235:genetics*; D006410:Hematopoiesis / Q000502:physiology*; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008962:Models, Theoretical; D051881:Receptor, Notch1 / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D051898:Smad1 Protein / Q000378:metabolism; D051905:Smad6 Protein / Q000378:metabolism; D013816:Thermodynamics; D014157:Transcription Factors / Q000378:metabolism
chemical_list: C525810:Bmp4 protein, mouse; D055415:Bone Morphogenetic Protein 4; D050676:Core Binding Factor Alpha 2 Subunit; C497762:Notch1 protein, mouse; D051881:Receptor, Notch1; C493726:Runx1 protein, mouse; D051898:Smad1 Protein; C497401:Smad1 protein, mouse; D051905:Smad6 Protein; C497803:Smad6 protein, mouse; D014157:Transcription Factors